Virtual Library

Background:
Patient prognosis after complete resection for pathologic stage IIIA(N2) non-small cell lung cancer (NSCLC) remains a significant concern. Accumulating evidence suggests that the host immune response might determine tumor behavior and influence the survival prognosis; however, the clinical relevance of the host immune response to NSCLC has yet to be established. We aimed to investigate the prognostic value of tumor-infiltrating lymphocytes (TILs) in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC.

Methods:
From January 2005 to June 2012, all consecutive patients with pathologic stage IIIA(N2) NSCLC who underwent complete resection in our hospital were retrospectively reviewed. Inclusion criteria for this study were as follows: complete resection through a surgical procedure of either lobectomy or pneumonectomy with microscopically tumor-free resection margins; systematic nodal dissection with a minimum of three N2 stations dissected; and histologically proven NSCLC of stage pT1-3N2M0 (according to the 7th UICC TNM classification). Patients who received neoadjuvant chemotherapy and/or radiotherapy were excluded. Full-face hematoxylin- and eosin-stained sections from surgical specimens from each case were evaluated for the density of TILs by two qualified specialized pathologists. A published recommended TILs scoring scale was followed. The degree of lymphocyte infiltration into the tumor was scored as none (score 0), low (score 1), moderate (score 2), or high (score 3). Patients were stratified into TIL-negative (none to low infiltration) or TIL-positive (moderate to high infiltration) group based on pathologic evaluation.

Results:
Of the eligible 320 patients included in the analysis, 135 (42%) patients were categorized as TIL-positive; and the 185 (58%) patients were defined as TIL-negative. The median follow-up duration was 30.8 months (range, 12-101.4 months) for the living patients. In the entire cohort, the median survival time (MST) was 42.5 months, and the 1-, 3-, and 5-year overall survival (OS) rates were 90.9%, 54.3%, and 35%, respectively. For the patients in the TIL-negative and TIL-positive groups, the MST was 35.7 and 45.5 months, respectively. The 1-, 3-, and 5-year OS rates were 88.6%, 49.5%, and 34%, respectively, in the TIL-negative group and 94.1%, 61.2%, and 35.6%, respectively, in the TIL-positive group. A higher density of TILs (TIL-positive) was associated with improved OS and the differences trended toward significance (P=0.06). Multivariate analyses confirmed that TIL-positive was an independent prognostic factor for improved OS (HR=0.70, 95%CI 0.50-0.99, P=0.05). Subgroup analyses indicated that this positive effect was the greatest for patients with squamous cell carcinoma (SCC; HR=0.44, 95%CI 0.21-0.94, P=0.03). Of the 93 patients with SCC, TIL-positive was significantly associated with improved distant metastasis-free survival (DMFS; P=0.02) and OS (P=0.03). The TIL-positive was a strong prognostic factor in the multivariate model, both for prolonged DMFS (HR=0.39, 95%CI 0.17-0.87, P=0.02) and OS (HR=0.47, 95%CI 0.22-1.00, P=0.05).

Conclusion:
Our data suggested a potential role of TILs in predicting the survival prognosis of patients with completely resected stage IIIA(N2) NSCLC. The beneficial effects of TILs were more pronounced for the prediction of DMFS and OS in patients with SCC. Studies assessing outcomes and therapeutic efficacies in prospective clinical trials should consider stratification for this immunological parameter.

Background:
Inhibition of the PD1/PD-L1 axis has been successfully developed in advanced NSCLC, and its role in locally advanced NSCLC is under investigation. The prognostic and predictive values of PD-L1 expression is still debated in advanced NSCLC and unknown in stage III NSCLC patients definitely treated by CRT

Methods:
We reviewed all consecutive patients that received CRT or RT with a curative intentfor stage III NSCLC in a single institution. Paraffin embedded tissue block were collected, immunohistochemistry was performed on a Ventana Benchmarck Ultra platform using the E1L3N clone (Cell Signaling Technologies). All tumors were centrally reviewed and tumor cells were scored accordingly (Herbst et al., Nature 2014).Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for performance status (0, ≥1), stage (IIIA, IIIB) and thoracic surgery (yes, no). Median follow-up was estimated by the Schemper method

Results:
Between January 2002 and June 2013, clinical data from 190 patients were collected. Median dose of RT was 66 Gy (46-70). Chemotherapy, mostly based on doublets with platin salt was administrated concomitantly in 108 patients, as induction/consolidation treatment in 170 patients, and 15 patients did not receive any chemotherapy. Fifty NSCLC were evaluable for PD-L1 expression, 22 (44%) being positive. Fourteen (28%) were female, 24 (48%) were current-smoker, 17 (34%) had adenocarcinoma and there were 23/27 stage IIIA/IIIB. Evaluable and unevaluable populations for PD-L1 were not different. There were no clinical or pathological factors related to PD-L1 positivity. Median follow-up was 7.6 years (minimum: 0.7 year). Median OS was 1.1year(95% confidence interval (CI) 0.6-1.5) in PD-L1 positive (pos) and 2.0 years (95% CI 1.5-3.8) in PD-L1 negative (neg) (p=0.01), HR=2.3 (95% CI 1.2-4.5, p=0.01). Median PFS was 0.7 year (95% CI 0.6-0.8) in PD-L1pos and 1.0 year (95% CI 0.8-1.5) in PD-L1neg (p=0.04), HR=2.1 (95% CI1.1-4.0, p=0.03). There was no difference in terms of acute toxicity according to PD-L1 status (positive or negative):25 had oesophagitis (grade≥2) and 16 had pneumonitis (p=0.57 and p=0.23 respectively).

Conclusion:
PD-L1 positivity was associated to a poorer survival in stage III NSCLC patients treated by definitive chemo-radiotherapy. Its prognostic and/or predictive value should be further evaluated in this population.

Abstract not provided

Background:
The indolinone small-molecule derivative nintedanib has been originally designed as an anti-angiogenic drug targeting the receptor tyrosine kinases VEGFR, FGFR and PDGFR for the treatment of cancer. Additionally, preclinically nintedanib has demonstrated potent anti-fibrotic and anti-inflammatory activity. Nintedanib was recently approved in the US and EU for the treatment of idiopathic pulmonary fibrosis (IPF). The aim of this study was to assess the efficacy and safety of nintedanib in a mouse model of partial lung irradiation.

Methods:
266 C57BL/6 adult male mice were irradiated with a single fraction radiation dose of 0, 4, 8, 12, 16 or 20 Gy using 5-mm circular parallel-opposed fields targeting the upper right lung with a precision image-guided small animal irradiator (PXRAD225Cx, PXI Inc, USA) sparing heart and spine based on micro-CT images acquired at 200 µm resolution. One week post irradiation, mice were randomized across nintedanib daily oral gavage treatment with 0, 30 or 60 mg/kg respectively for a total of 39 weeks. Micro-CT imaging was repeated on a monthly basis. At the end of the experiment, lungs were removed and processed for H&E, Van Gieson’s and Masson’s trichrome staining to evaluate the fibrotic phenotype.

Results:
Increased lung density could be visually observed by CT in the late stage imaging time points of irradiated mice after 20 Gy and was spatially limited to the irradiated portion of the lung. This increased density was consistent with the development of fibrosis, confirmed by an increased fibrotic phenotype scored by an increase in alveolar wall thickness, interstitial edema, interstitial and perivascular fibrosis and inflammation, interstitial and alveolar macrophages, atelectasis and vasculitis. Although no macroscopic decrease in CT density could be observed, nintedanib was able to reduce the microscopic fibrotic phenotype, in particular interstitial edema, interstitial and perivascular fibrosis and inflammation and vasculitis, without adverse effects.

Conclusion:
Nintedanib efficiently and safely reduces radiation-induced lung fibrosis after partial lung irradiation. Since, as expected, nintedanib did not affect alveolar wall thickness and macrophage involvement, no significant changes in lung density could be observed by CT imaging. Based on its protective effect, nintedanib might be safely introduced in clinical trials for patients treated with irradiation to the lungs.

Background:
Minimally invasive lobectomy has become the standard of care approach for early stage non-small cell lung cancer (NSCLC); however video assisted thoracoscopic (VATS) lobectomy after induction therapy remains controversial. We sought to evaluate perioperative outcomes of VATS and open lobectomy after induction therapy using a national database.

Methods:
A cohort study of patients that underwent VATS and open lobectomy after induction chemotherapy and/or radiotherapy was conducted using the National Surgical Quality Improvement Program (NSQIP) database from 2005 through 2012. Perioperative complications and mortality were compared between groups. Comparisons were made using two-sided student’s t-test or chi square test as appropriate.

Results:
A total of 6730 patients underwent lobectomy during the study period and 166 patients had prior induction therapy (open = 132, VATS = 34). There were no statistically significant differences in age, comorbidities or ASA class between groups. There were no significant differences in the surgeon specialty between groups (cardiac, thoracic, general, and vascular). Operative time was similar (VATS: 228 minutes, Open: 190 minutes; p = 0.07). Perioperative complications, return to OR, respiratory complication, mortality, and hospital length of stay were similar between groups. Table 1. Patient Demographics

N (%)	All (N = 166)	Open (N = 132)	VATS (N = 34)	P-value
Age, yrs; Mean (SD)	62.9 (10.2)	62.4 (10.7)	65.2 (7.6)	0.077
Female	88 (53)	72 (55)	16 (49)	0.563
Diabetes	16 (10)	11 (8)	5 (15)	0.325
COPD	35 (21)	26 (20)	9 (27)	0.479
Creatinine > 1.2	17 (10)	13 (10)	4 (12)	0.757
ASA Class ≥4	18 (11)	14 (11)	4 (12)

VATS = video assisted thoracoscopic, COPD = chronic obstructive pulmonary disease, ASA= American Society of Anesthesia class Table 2. Post-Operative Outcomes

N (%)	All (N = 166)	Open (N = 132)	VATS (N = 34)	P-value
LOS, days; mean (SD)	7.3 (6.1)	7.4 (6.1)	6.6 (6.3)	0.471
Wound complication	5 (3)	5 (4)	0	0.584
Pneumonia	16 (10)	15 (11)	1 (3)	0.197
Reintubation	18 (11)	15 (11)	3 (9)	1.000
Respiratory complication	25 (15)	22 (17)	3 (9)	0.419
Return to OR	15 (9)	14 (11)	1 (3)	0.311
In hospital mortality	9 (5)	8 (6)	1 (3)	0.687
30 day mortality	13 (8)	12 (9)	1 (3)	0.471

VATS= video assisted thoracoscopic, LOS = length of stay, OR= operating room

Conclusion:
This is the first review of a prospective national database comparing outcomes for VATS and open lobectomy after induction therapy for NSCLC. VATS lobectomy appears to be safe with no increased morbidity or mortality compared to open in patients that had prior induction therapy. A larger series of matched VATS and open approaches after induction therapy is needed.

Background:
[68]Ga-V/Q PET/CT is a novel imaging modality for assessment of perfusion(Q), ventilation(V) and lung density changes in the context of radiotherapy (RT) for non-small cell lung cancer.

Methods:
In a prospective clinical trial, 20 patients underwent 4D-V/Q PET/CT before treatment, 4 weeks into treatment and 3 months after definitive lung RT. Eligible patients were prescribed 60 Gy in 30 fractions with or without concurrent chemotherapy. Functional images were registered to the RT planning 4D-CT and isodose volumes averaged into 10 Gy bins. Within each dose bin, relative loss in SUV was recorded for ventilation and perfusion, and loss in air-filled fraction was recorded to assess RT-induced lung fibrosis. A dose-effect relationship was described using both linear and 2-parameter logistic fit models and goodness of fit assessed using Akaike Information Criterion (AIC).

Results:
A total of 179 imaging datasets were available for analysis (1 scan unrecoverable). An almost perfectly linear dose-response relationship was observed for perfusion and air-filled fraction (r[2] = 0.99, p < 0.01), with ventilation also strongly linear (r[2] = 0.95, p < 0.01) [Figure]. Logistic models did not provide a better fit as evaluated by AIC [Table]. Perfusion, ventilation and the air-filled fraction changed by -7.5% ± 0.3%, -7.1% ± 0.6% and 4.9% ± 0.02% per 10 Gy, respectively. Within high-dose regions, higher baseline SUV was associated with greater rate of loss. At 50Gy and 60Gy the rate of loss was 1.35% (p = 0.07) and 1.73% (p = 0.05) per SUV, respectively. Of 8/20 patients with peri-tumoral reperfusion / re-ventilation during treatment, 7/8 did not sustain this effect post-treatment. Figure 1 Figure 2





Conclusion:
RT induced regional lung functional deficits occur in a dose dependent manner and can be estimated using simple linear models with 4D-V/Q PET/CT imaging. These findings may inform functional lung sparing by planning RT using this novel imaging technology.

Background:
A national quality assurance program was conducted in order to compare standard radiation treatment plans for locally advanced non-small cell lung cancer (NSCLC) patients in Denmark.

Methods:
The five participating centres represented 71% of all radiotherapy centres in Denmark. They were provided with the CT images and delineations of GTV, CTV, PTV and organs at risks for five different NSCLC patients. Each centre created treatment plans based on the following optimization objectives: required dose distribution for target coverage 95%-107% of the prescribed dose of 66Gy/33fr to at least 95% of the PTV volume (90% for volume located in lung tissue); constraints for organs at risks D(max) < 50Gy to the spinal cord, D(max) < 70Gy to the oesophagus, V50 < 20% to the heart, V20 < 35% and D(mean) < 20Gy for the total lung volume (excluding the GTV). The treatment planning was done in accordance with the local centre practice; i.e. choice of IMRT versus VMAT, coplanar vs. non-coplanar technique, feasible functionalities for treatment planning optimisation (mean value versus different points at the DVH curve), and any additional local dose constraints (e.g. D(max) < 45Gy to spinal cord and/or V5 < 60% to the total lung volume). Finally, all treatment plans were collected and analysed cooperatively.

Results:
All objectives for target coverage and organs at risk were met. There was a wide variability in the dose volume histograms (DVHs) for some of the organs at risk, especially the lungs. This is illustrated in the figure, where the lung DVH from seven different treatment plans, created for the same patient by the five participating centres, is shown. The lung DVHs are overlapping around 20Gy, as all centres had a dose constraint on V20. Some centres had an additional local dose constraint on V5, which resulted in decreased doses to the lungs and increased doses to the mediastinal structures compared with centres that had no dose constraints on V5 for the lungs. Figure 1



Conclusion:
Differences in the dose distribution to the organs at risk can have an impact on treatment morbidity (e.g. pneumonitis, oesophagitis). These differences were seen for standard treatment plans, which are often used in multicentre clinical trials as the baseline compared to an experimental arm, where such differences can be even more pronounced. It is highly recommended to perform test runs across centres prior to entering clinical trials in order to uncover differences as the ones presented.

Abstract not provided

Background:
The tropomyosin-receptor kinase (TRK) family includes genes important in nervous system development, NTRK1 (N1), NTRK2 (N2) and NTRK3 (N3). Oncogenic activation was identified long ago as N1 fusions in colon cancer and numerous fusions have been recently identified affecting all family members in multiple tumor types. This study developed FISH reagents for molecular diagnosis of NTRK rearrangements and investigated their prevalence in NSCLC. The ultimate goal is to validate a clinical assay for selection of patients who may benefit from novel tyrosine kinase inhibitors (TKIs) targeting these fusion proteins.

Methods:
Three FISH break-apart (BA) probe sets (LDTs) were tailored for diagnosis of rearrangements in N1, N2 and N3 and tested in specimens with known genomic status for these genes: cell lines KM12 (N1), CUTO3 (N1), MO-91 (N3), xenograft CULC001 (N1), and clinical specimens, and used to screen resected NSCLC. The LSI NTRK1 Cen and Tel probes (Abbott Molecular) were also tested. A specimen was positive for individual rearrangement when ≥15% tumor cells had split or single 3’,5’ signals. Moreover, a 6-target, 2-color FISH probe including the 3’N1, 3’N2 and 3’N3 sequences labeled in red and the 5’N1, 5’N2 and 5’N3 sequences labeled in green (TRKombo) was designed for rapid screening of TRK rearrangements in clinical specimens.

Results:
Results were obtained in 443, 410, and 434 examined NSCLC and positive patterns were detected in 5, 5 and 1 specimens, respectively for N1, N2, and N3. These 11 positive patients had age ranging from 38y to 76y, gender 6 male:5 female, and were current (4), former (5) or never (2) smokers. Histology was predominantly adenocarcinoma (7) but also included squamous cell (3) and neuroendocrine morphology (1). Unique to the N1 assay was the observance of FISH signal fusions where the 5’N signals appeared as doublet in >20% of the NSCLC specimens, which was determined to be copy number variation due to segmental duplication. Other atypical patterns were observed for all three targets and included doublets of the FISH fusion signals (18%, 14% and 9% respectively) and gene clusters (~5% for each). Twenty specimens (pre-clinical models and clinical cases) characterized as positive by the LDT N1 and by next generation sequencing (NGS) or atypical by the LDT NTRK1 BA were blindly analyzed with the LSI NTRK1 probe set and the results were reproducible, with brighter intensity of the fluorescent signals for the LSI probe. These specimens (positive by FISH and several atypicals) are currently under investigation to characterize the sequence specific genomic rearranged region by using a custom targeted, capture-based NGS panel (NimbleGen, Roche). The TRKombo screening probe performed well in blinded experiment using validation set including pre-selected positive and negative specimens and is under testing in clinical tissue sections.

Conclusion:
N1, N2 and N3 fusions were detected by FISH in a subset of lung carcinomas including adeno, squamous and neuroendocrine tumors. Optimization of molecular panels for diagnosis of these rearrangements is relevant since they represent a sizeable number of cases across multiple tumor types and there are numerous targeted inhibitor agents under development.

Background:
PTPN11/Shp2 somatic mutations occur in 25% of Juvenile myelomonocytic leukemias (JMML) and less commonly in adult solid tumors. PTPN11/Shp2 activates the mitogen-activated protein kinase (MAPK) and the phosphatidylinositide 3-kinase (PI3K) pathways. Accordingly, PTPN11/Shp2 mutations were shown to sensitize leukemia cells to MEK and PI3K inhibitors.

Methods:
We applied mass-spectrometry based genotyping (Sequenom Inc., Germany) to DNA extracted from tumor and matched normal tissue of 356 NSCLC patients (98 adenocarcinomas and 258 squamous cell (SCC)). PTPN11/Shp2 constructs with mutations (E76A, A72D) were generated and stably expressed in IL-3 dependent BaF3 cells and NSCLC cell lines (H1703, H157). The acquisition of MAPK and PI3K pathways activation was evaluated using western blotting and reverse phase protein array (RPPA). PTPN11/Shp2 phosphatase activity was measured in whole cell protein lysates using Shp2 assay kit (R&D Systems).

Results:
Somatic PTPN11/Shp2 hotspot mutations occurred in 3 (3.1%) and 9 (3.4%) of adenocarcinomas and SCCs, respectively. Mutant PTPN11/Shp2, compared to PTPN11/Shp2 wild type, promoted ten-fold IL-3 independent BaF3 cell survival. BaF3, H1703, and H157 cells expressing mutant PTPN11/Shp2 exhibited increased PTPN11/Shp2 phosphatase activity, phospho-ERK1/2, and phospho-AKT levels. Sequencing of NSCLC cell lines revealed that NSCLC H661 cell line has a PTPN11/Shp2 activating mutation (N58S). H661 had significantly higher PTPN11/Shp2 phosphatase activity when compared to PTPN11 wild-type H1703 and Calu3 NSCLC cells. Since the biological functions of PTPN11/Shp2 are mediated through its phosphatase domain, we stably expressed the inactivating PTPN11/Shp2 phosphatase domain mutation (C459S) in H661, H1703 and H157 cells resulting in catalytically inactive PTPN11/Shp2. This led to decreased phospho-ERK1/2 levels in all three cell lines. Importantly, the inactivation of PTPN11/Shp2 resulted in decreased phospho-AKT levels in H661 cells (PTPN11-mutated) and had no effect on phospho-AKT levels in the PTPN11/Shp2-wild type H1703 and H157 cells. Taken together, this data suggests that PTPN11/Shp2 activating mutations are oncogenic in NSCLC cells. Moreover, these findings reveal that PTPN11/Shp2 mutations may selectively activate the PI3K pathway in NSCLC cells. Parental H661 (PTPN11-mutated, KRAS and PIK3CA-wild type), parental H1703 (PTPN11, KRAS and PIK3CA-wild type) and parental H157 (KRAS-mutated, PTPN11 and PIK3CA-wild type) cells were treated with the novel MEK (BAY86-9766) and PI3K (BAY80-6946) inhibitors. IC50 values (table 1) suggest that PTPN11-mutated NSCLC cells have modest sensitivity to MEK inhibitors and profound sensitivity to PI3K inhibitors.

Table 1 IC 50 valuse

Cell Line	BAY86-9766 (nM)	BAY80-6946 (nM)
H661	2880 ± 600	13 ± 4.7
H157	1450 ± 520	< 50% inhibition @ 200
H1704	< 50% inhibition @ 10000

Conclusion:
PTPN11/Shp2 demonstrates the in vitro features of a driver oncogene, and potentially represents a new target in NSCLC.

Abstract not provided

Background:
Amplifications and activating mutations in the c-MET proto-oncogene are known oncogenic drivers that have proven responsive to targeted therapy. Mutations causing skipping of MET exon 14 are also oncogenic, but less well characterized. We undertook comprehensive genomic profiling (CGP) of a large series of advanced cancers to further characterize MET exon 14 alterations.

Methods:
DNA was extracted from 40 microns of FFPE sections from 38,028 advanced cancer cases. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of >500x using three versions of the FoundationOne test. Hybridization capture baits for the MET gene were identical for all three versions of the test. Base substitution, indel, copy number alteration, and rearrangement variant calls were examined to identify those nearby to the splice junctions of MET exon 14. These genomic alterations were then manually inspected to identify those likely to affect splicing of exon 14, or delete the exon entirely.

Results:
221 cases harboring MET ex14 alterations were identified. These patients had a median age of 70.5 years (range 15-88), with 97 males and 124 females. The cases were lung carcinoma (193), carcinomas of unknown primary (15), brain glioma (6), and one each of adrenal cortical carcinoma, hepatocellular carcinoma, histiocytic sarcoma, renal cell carcinoma, rhabdomyosarcoma, skin merkel cell carcinoma, and synovial sarcoma. The majority were stage IV. Identification of this alteration has lead to treatment with MET inhibitors such as crizotinib, and to durable partial responses or better exceeding 3 months in histiocytic sarcoma (1), sarcomatoid lung carcinoma (1), and nsclc (1+). Multiple patients (5+) have initiated treatment on either crizotinib or MET inhibitors in clinical development, and additional outcome data will be reported. One patient with locally advanced unresectable disease harbored a MET exon 14 skipping alteration. On initiation with treatment with an MET inhibitor, symptomatic relief was observed in 3 days, radiographic response was observed at two weeks, and resection was performed 8 weeks after initiation of the MET inhibitor.

Conclusion:
MET exon 14 alterations define a hereto unrecognized population of advanced cancer cases, particularly in NSCLC. Multiple case reports demonstrate that these alterations confer sensitivity to multiple small molecule MET inhibitors. This finding expands the population of advanced NSCLC patients who can derive benefit from MET-targeted therapies.

Background:
The reported prevalence of MET gene amplification in non-small cell lung cancer (NSCLC) varies from 0-21% and clinical correlations are emerging slowly. In a well-defined NSCLC cohort of the ETOP Lungscape program, we explore the epidemiology, the natural history of MET amplification and its association with MET overexpression, overall survival (OS), relapse-free survival (RFS) and time to relapse (TTR).

Methods:
Resected stage I-III NSCLC, identified based on the quality of clinical data and FFPE tissue availability, were assessed for MET gene copy number (GCN) and expression analysis using silver in-situ hybridization (SISH) and immunohistochemistry (IHC), respectively, on TMAs (MET and centromere-specific probes; anti total c-MET antibody, clone SP44; Ventana immunostainer). MET amplification was defined as MET/centromere ratio ≥2 with average MET GCN ≥4, high MET GCN at two levels as ≥median CGN and ≥5 (irrespective of amplification) and MET IHC+ as 2+ or 3+ intensity in ≥50% of tumor cells. Sensitivity analysis to define the amplification’s thresholds was also performed. All cases were analysed at participating pathology laboratories using the same protocol, after successful completion of an external quality assurance (EQA) program.

Results:
Currently 2709 patients are included in the Lungscape iBiobank (median follow-up 4.8 years, 53.3% still alive). So far, 1547 (57%) have available results for MET GCN with amplification detected in 72 (4.7%; 95%CI: 3.6%, 5.7%) and high MET GCN (≥5) in 65 (4.2%; 95%CI: 3.2%, 5.2%). The median value of average MET GCN per cell is 2.3. IHC MET expression is available for 1515 (98%) of these cases, 350 (23%) of which are MET IHC positive [170 cases (49%) 3+, 180 (51%) 2+]. The median age, for the cohort of 1547 patients, is 66.2 years, with 32.8% women, and 13.5%, 29.7%, 54% never, current, former smokers, respectively. Stage distribution is: IA 23.6%, IB 24.6%, IIA 17%, IIB 12.1%, IIIA 20.9%, IIIB 1.8%, while 52.7%, are of adenocarcinoma and 40.0% of squamous histology. MET amplification and high MET GCN (≥5) are not significantly associated with any histological tumor characteristics or stage (multiplicity adjusted alpha: 0.005). High MET GCN (≥2.3) is less frequent in current smokers (38.3% vs. 55.6% for former or non-smokers, p<0.001). MET amplification and high MET GCN are significantly associated with IHC MET positivity (p<0.001 in all cases). MET amplification is present in 9.7% of IHC MET+ vs 3.1% of IHC MET- patients and high MET GCN (≥5) in 8.6% of IHC MET+ vs 2.8% of IHC MET- patients. MET amplification ranges from 0 to 16% between centers, while high MET GCN (≥5) and (≥2.3) from 0% to 12%, and 11.8% to 98.9%, respectively. MET amplification and both levels of high MET GCN are not associated with OS, RFS or TTR.

Conclusion:
The preliminary results for this large, predominantly European, multicenter cohort demonstrate that MET amplification assessed by SISH prevails in 4.7% of NSCLC, is associated with strong MET expression, and has no influence on prognosis. The large inter-laboratory variability in GCN despite EQA efforts may highlight a critical challenge of MET SISH analysis in routine practice.

Background:
Increases in MET copy number define an oncogenic driver state sensitive to MET inhibition (Camidge et al, ASCO 2014). However, the level at which the genomic gain is relevant remains uncertain. When testing is performed by fluorescence in situ hybridization (FISH), variable cut-points in both mean MET/cell and MET/CEP7 ratio have been used. Partially overlapping datasets from the Lung Cancer Mutation Consortium (LCMC1) and Colorado Molecular Correlates (CMOCO) Laboratory were explored for a distinct MET-copy number driven lung adenocarcinoma subtype.

Methods:
MET was assessed by FISH. Data from non-adenocarcinomas and EGFR mutant patients with acquired resistance to an EGFR inhibitor were excluded. Positivity criteria were mean MET/cell ≥5 (low ≥5-<6, intermediate ≥6-<7, high ≥7) or MET/CEP7 ≥1.8 (low ≥1.8-≤2.2, intermediate >2.2-< 5, high ≥5). MET metrics were compared by race, sex, smoking status, stage at diagnosis, number of metastatic disease sites, site of metastases, presence of other known drivers (EGFR, KRAS, ALK, ERBB2, BRAF, NRAS, ROS1 and RET), response to first line chemotherapy and overall survival using Fisher’s exact tests, chi-square tests, Spearman correlations and log-rank tests, as appropriate. Statistical significance was set at the 0.05 level without adjustment for multiple comparisons.

Results:
1164 unique adenocarcinomas were identified (60% female, 85% Caucasian, 66% ex/current smokers). MET/CEP 7 data was available on 1164 and mean MET/cell on 700. 52/1164 (4.5%) had MET/CEP7 ≥1.8 (48% female, 83% Caucasian, 69% smokers). 50/52 (98%) had ≥1 other oncogenic driver tested (25/50 (50%) positive). 113/700 (16%) had mean MET/cell ≥ 5 (57% female, 82% Caucasian, 58% smokers). 109/113 (96%) had ≥ 1 other oncogenic driver tested (73/109 (67%) positive). Among patients with ≥1 additional driver oncogene tested, alternate drivers in low, indeterminate and high categories of mean MET/cell were 44/60 (67%), 17/24 (70%) and 12/28 (43%) respectively and for MET/CEP7: 16/29 (55%), 9/18 (50%) and 0/4 (0%) respectively. MET positive with additional drivers were excluded from further analyses. Men exceeded women in MET/CEP7 (men 4% vs women 1.6%, p = 0.019) and mean MET/cell positive cases (men 9.6% vs women 5.4%, p = 0.058). 6.4% of adrenal metastasis cases were MET/CEP7 positive vs 2% all other sites, p=0.031. Mean MET/cell: 12% adrenal vs 5% other sites, p=0.082. MET/CEP7 or mean MET/cell positive and negative groups did not differ by other variables (p > 0.05).

Conclusion:
The proportion of ‘MET positive’ adenocarcinomas varies by definition and positivity cut-point. Mean MET/cell ≥5 defines nearly 4x more positives than MET/CEP7 ≥1.8 and no mean MET/cell positive category was free from overlap with other drivers. As only high MET/CEP7 had no overlap with other drivers, MET/CEP7 ≥ 5 is the clearest candidate for a pure MET-copy number driven state, however cases free from other drivers do exist at lower MET positivity levels. MET/CEP7 positive cases free from other known drivers are more likely to be male, but unlike other known oncogenic states, race and smoking status are not significant in determining positivity. MET positivity may have a specific biological phenotype, being more likely to present with adrenal metastases.

Background:
MET is a receptor tyrosine kinase with frequently activated signaling in lung cancers. Multiple studies indicate that MET overexpression correlates with poor clinical prognosis. Tumors with MET amplification and overexpression may respond better to MET inhibitors than tumors with low expression. The prevalence of MET overexpression in lung cancer cohorts has varied from 20%-80%, as has the proportion of patient’s testing positive for prospective clinical trials with entry based on MET overexpression. The Lung Cancer Mutation Consortium (LCMC) Pathologist Panel endeavored to standardize evaluation of MET protein expression with “Round Robin” conferences.

Methods:
508 FFPE non-small cell lung cancer specimens were stained by immunohistochemistry for MET protein expression (SP44 antibody, Ventana). Seven pathologists from LCMC sites with specialized training in MET scoring evaluated 78 Aperio-scanned images of MET-stained slides in two successive rounds of 39 different cases per round. The percentage of tumor cells with membranous and/or cytoplasmic staining at different intensities were evaluated with H-scores ranging from 0 to 300. Overall group and individual pathologist’s scores were compared with intraclass correlation coefficients (ICCs). Between rounds, a “Round Robin” teleconference was conducted to review discordant cases and improve consistency of scoring. Steps to improve scoring included: review of a Roche MET training document, sharing pictures of cases with concordant scores (Figure 1), and provision of H&E images for the second round to facilitate identification of tumor areas. Figure 1



Results:
The overall average MET H-score for the 78 cases was 165.3 (H-score range: 42.5-279.7). The average H-score was <125 for 14 specimens, 125-175 for 35 specimens, and >175 for 29 specimens. The overall group ICC comparing the consistency of H-scores from all 7 pathologists improved from 0.50 (95% confidence interval: 0.37-0.64, “fair” correlation) for the first scoring round to 0.74 (95% confidence interval: 0.64-0.83, “good” correlation) for the second round. A comparison of the individual pathologist’s ICCs demonstrated improved individual scoring consistency for all seven pathologists between rounds with an average of 0.64 (“moderate” correlation, range 0.43-0.76) for the first round and 0.82 (“almost perfect” correlation, range 0.75-0.93) for the second round.

Conclusion:
Development of standardized, reproducible strategies for evaluation of complex biomarkers, such as MET, are critical to clinical trial design. The consistency of scoring for MET protein expression and other biomarkers may be improved by continuous training and communication between pathologists with easy access to H&E images and other visual aids.

Abstract not provided

Background:
Plasma genotyping of cell-free DNA (cfDNA) has the potential to allow for noninvasive genotyping while avoiding the inherent shortcomings of tissue genotyping and repeat biopsies. We have developed a quantitative droplet digital PCR (ddPCR)-based plasma genotyping assay capable of detecting common EGFR and KRAS mutations in NSCLC (Oxnard et al., CCR 2014). Although rapid and highly specific, this assay lacks the ability to both multiplex and detect complex genomic alterations such as rearrangements. In this prospective study, we evaluate the test characteristics of ddPCR combined with plasma next-generation gene sequencing (NGS) as a new paradigm for plasma genotyping.

Methods:
Patients with newly diagnosed advanced NSCLC were eligible. All patients were required to have a biopsy available or planned for tissue genotyping which was used for gold standard comparison. Patients underwent an initial blood draw and immediate plasma ddPCR for EGFR exon 19 del/L858R and KRAS G12X. A subset of patients additionally underwent plasma NGS using a unique probe set designed by our group to detect rearrangements and mutations in 12 genes (EGFR, KRAS, ALK, ROS1, BRAF, RET, NRAS, ERBB2, MET, MEK1, PIK3CA and p53). This plasma NGS assay utilized a novel bias corrected NGS which minimizes off-target reads (Resolution Bio) performed on a desktop MiSeq platform. Test turnaround time (TAT) was measured in business days from date of blood draw until test reporting.

Results:
120 patients with newly diagnosed advanced NSCLC have been enrolled and 94 have completed tissue and plasma genotyping. Tumor genotype included 25 EGFR exon 19/L858R mutants, 17 KRAS G12X mutants, 24 rare genotypes and 15 others. Median TAT for plasma ddPCR was 3 days (range 1-5). Specificity of plasma ddPCR was 99% for EGFR exon 19 del/L858R (68/69) and 100% for KRAS (77/77). Sensitivity of plasma ddPCR was 76% for EGFR exon 19 del/L858R (19/25) and 71% for KRAS (12/17). Plasma NGS is ongoing with testing completed on 11 patients with a known tumor genotype. 8 had a genotype detected on plasma NGS: 2 ALK rearrangements, 1 ROS1 rearrangement, 1 RET rearrangement, an EGFR G719A mutation, a KRAS G12C and a combined KRAS G12C/PIK3CA mutation - all matched the tumor genotype. Preliminary plasma NGS turnaround time ranged from 5-10 business days.

Conclusion:
Rapid plasma genotyping using sequential plasma ddPCR (1-5 day TAT) followed by plasma NGS (5-10 day TAT) represents a new paradigm for noninvasive plasma genotyping. This approach capitalizes on the use of rapid ddPCR for common targetable mutations and the ability of plasma NGS using an augmented MiSeq platform to multiplex and detect complex alterations. This new model for plasma genotyping uses testing platforms that can readily be employed in most molecular pathology laboratories allowing for widespread adoption.

Background:
The National Comprehensive Cancer Network (NCCN) non-small cell lung cancer guidelines recommend testing for seven genomic targets amenable to matched therapies, including point mutations and insertions/deletions (indels) in EGFR and ERBB2 (HER2), point mutations in BRAF, fusions in ALK, RET and ROS1, and amplification of the MET gene. Novel digital sequencing technology allows assessment of these biomarkers without an invasive tissue biopsy.

Methods:
We prospectively tested cell free DNA from 43 advanced non-small cell lung cancer patients using a cell-free circulating tumor DNA (ctDNA) next-generation sequencing (NGS) panel of 54 cancer genes (Guardant360). Single nucleotide variants (SNVs) in 54 genes and copy number variants (CNVs) in 3 genes (EGFR, ERBB2 and MET) were reported quantitatively as the mutant allele fraction (MAF) in cell-free DNA and the absolute copy numbers in plasma, respectively.

Results:
79% of patients had at least one ctDNA alteration detected. Five (11.6%) had sensitizing mutations in EGFR: EGFR L858R (n=1), EGFR exon 19 deletions (n=4), which may respond to first line tyrosine kinase inhibitors (TKIs) such as erlotinib and afatinib. Three patients with EGFR exon 19 deletions had concurrent T790M resistance mutations, which develop in over half of patients on early generation TKIs. MET amplification, which may respond to crizotinib, was identified in one patient. Clinical outcomes will be reported at the time of presentation. Of the 43 patients in our series, actionable findings were identified in 35 patients (81.4%), with an approved therapy in 5 (11.4%), off label therapies in 19 (44.2%), and clinical trials in 28 (65.1%).

Conclusion:
In our series of NSCLC patients with advanced disease, digital sequencing of cell-free circulating tumor DNA yielded results in approximately 80% of patients. Of these, over 80% had an actionable alteration, including 5 cases with EGFR alterations that could benefit from an approved therapy. Biopsy-free comprehensive sequencing of a patient’s cancer can empower informed treatment decisions from a simple blood draw, especially when repeat tissue biopsy is not feasible or tissue NGS is uninformative.

Background:
Chromosomal rearrangements that result in transcript fusions have been a focus of attention in cancer as they provide attractive therapeutic targets. Identifying tumors that harbor chromosomal rearrangements by in situ hybridization assays has been a challenge in the clinic because these assays demand large quantities of tissue specimens. Cell-free nucleic acids from patient plasma may provide a non-invasive, alternative tool for detecting transcript fusions. Here, we demonstrate the feasibility of detecting ALK fusions with a qRT-PCR assay using cell-free plasma RNA (cfRNA).

Methods:
We designed a one-tube, four-channel multiplex ALK qRT-PCR assay that incorporates two strategies to detect ALK fusions. One channel employs variant-specific primers to detect >90% of the reported ALK fusions. The remaining three channels measure the expression of the 5’ and 3’ ends of the ALK gene relative to an internal reference and to each other, in theory, permitting the detection of all ALK fusions including those without knowledge of the fusion partner. To assess the performance of the multiplex ALK prototype assay, we made contrived samples blending mutant and wildtype cell line RNAs. In addition, we tested the multiplex ALK assay on NSCLC FFPET specimens (n=209). Moreover, to mimic plasma cfRNA, we made contrived samples by blending mutant cell line conditioned media with normal plasma.

Results:
Data from the cell line RNA blends demonstrate that both the variant-specific and the 5’ and 3’ differential expression successfully detect the EML4-ALK fusion-positive RNA. The variant-specific component of the assay is sensitive enough to detect at least 25pg of fusion-positive cell line RNA at a 1:4000 dilution with wildtype cell line RNA. From the NSCLC FFPET specimens, we identified 4 samples positive for the ALK fusion. These results were validated by a reference method that uses anchored-PCR to enrich ALK targets followed by NGS that employs a novel algorithm to identify potential fusion products. In addition, the multiplex ALK qRT-PCR assay detected transcript fusions in blends composed of plasma and EML4-ALK positive conditioned media at a dilution of 3:1. Lastly, we tested the multiplex ALK assay on confirmed ALK-fusion positive NSCLC plasma specimens, and were able to detect ALK fusions (7 out of 8) from as little as 750 ul of plasma.

Conclusion:
In summary, we have developed a one-tube, multiplex ALK qRT-PCR assay that exhibits performance characteristics suitable for transcript fusion detection in plasma cfRNA. Efforts are underway to further test and optomize the performance of this assay in clinical samples and to apply this multiplex qRT-PCR design concept to other transcript fusions including RET and ROS1.

Abstract not provided

Background:
Circulating tumor DNA can be detected in urine efficiently, serially, and completely non-invasively. Utilizing a PCR enriched NGS detection platform, we sought to demonstrate the feasibility of detecting activating and resistance EGFR mutations in urinary ctDNA to understand mechanisms of resistance to targeted therapies in patients with EGFR-mutated lung adenocarcinoma.

Methods:
In a biomarker study of 46 patients enrolled, urine was collected every 3-6 weeks from patients on first line anti-EGFR TKI therapy and then daily at progression during the first week of 3rd generation anti-EGFR TKI treatment when available. Urinary ctDNA was extracted by a method that preferentially isolates short, fragmented ctDNA. Quantitative analysis of EGFR activating exon19del, L858R, and T790M resistance mutations was performed utilizing wild type blocker probes, PCR enrichment, and NGS detection (MiSeq). Early pharmacodynamic events within the first hours to days of anti-EGFR therapy were further studied by quantitating ctDNA mutations and comparing with the reponse or lack of response by RECIST on CT scans 6 weeks after initiation of second line therapy.

Results:
Interim analysis was conducted on 34 patients receiving first line anti-EGFR therapy with erlotinib. The average quantity of DNA obtained per patient was 830ng/70ml of urine. The sensitivity between tissue and urine for EGFR Exon19del, L858R, and T790M was 94%, 100%, and 100% respectively, and interim specificity was 94%, 100%, and 96% respectively. Analysis of longitudinal samples from patients on erlotinib revealed that the EGFR T790M mutation was detected in the urine of 17 out of 24 (71%) patients 4-15 weeks before radiographic progression on erlotinib. All 10 patients who were positive for T790M mutation by tissue were also positive by urine. Three patients were T790M tissue negative but urine was positive for T790M. Early peaks in EGFR Exon19del, L858R, and T790M ctDNA on days 1-4 of urine collected daily within the first week on next generation anti-EGFR TKI correlated with CT radiographic response or lack of response 6 weeks after first drug dosing. Figure 1



Conclusion:
We demonstrate that EGFR activating and resistance mutations can be detected in ctDNA in urine months before progression on anti-EGFR TKIs. Urinary ctDNA testing identifies additional patients who are potentially eligible for next generation anti-T790M treatment. The size of the peaks in ctDNA upon second line anti-EGFR inhibitors correlate with tumor lysis and CT radiographic response. The clinical utility of daily kinetic monitoring of ctDNA in urine after drug adminstration is being further validated in an expanded cohort.

Background:
To fully implement precision therapy in lung cancer, transition to a re-biopsy policy will be required at baseline and at progression after each line of therapy. The molecular testing paradigm is shifting toward next generation sequencing (NGS). As tissues are limited and repeat invasive biopsy introduces cost and risk, novel technologies sensitive and specific enough for multiplexed assessment in cell-free DNA (cfDNA) isolated from patient blood would represent a significant advance. Preliminary experience from investigators suggest a high degree of correlation between repeat tumor biopsy and plasma NGS. Here, we present the Guardant Health (GH) digital sequencing approach in a consecutive series of NSCLC cases.

Methods:
225 consecutive blood specimens from NSCLC patients, collected February–March 2015, were evaluated for cfDNA tumor alterations by digital sequencing using the GH panel of 68 genes. The test includes all reported fusion partners for ALK, RET, ROS1, and NTRK1 and cfDNA amplification for 16 genes. The mutant allele fraction (MAF) was calculated relative to WT in cfDNA. The test is sensitive to a single fragment of mutated cfDNA in a 10 ml blood sample and analytic specificity is >99.9999%.

Results:
Canonical EGFR activating mutations were detected in 20 cases (14 E19del, 3 L858R, 2 E20ins, 1 G719A). EGFR T790M co-occurred in 7 cases (6 E19del, 1 L858R), with EGFR amplification observed in 6 of the 20. Median age for patients with EGFR mut+ was 62.5; 18 female(90%), compared to nonEGFR-mutant cases. Four cases had driver fusions (2EML4-ALK, 2 KIF5B-RET) and five cases harbored an ERBB2 E20ins. KRAScodon 12/13 mutations were detected in 23 patients, while 3 harbored mutations in HRAS(Q61L) and NRAS(Q61L, G13R), and 6 had BRAF mutations (4 V600E, 2 G466X). All putative drivers were mutually exclusive. Mutations in signal transduction factors with confirmed gain-of-function activity included AKT1(E17K), MEK1(K57N, C121S), PIK3CA(E542K, E545K x2, H1047L, M1043V, R93W) and JAK2(V617F x2); truncating or missense mutations (>3% MAF) were observed in NF1 (6 cases), PTEN(1 case), SMAD4(4 cases) and STK11(4 cases). TP53 mutations were detected in 116/225 (51%). Evidence of gene amplification was seen in 32 cases, with 11 harboring multiple events. By function, amp events were observed for G1 cell cycle factors:11, RTKs: 17, MYC: 2; and signal transduction: 21. MAF ranged from 0.06% to 83.4% (av 5.1%; median: 9.8%), reflecting clinical and biologic diversity of patients. In a clinical subset at UC Davis, 27 patients were evaluated and alterations were detected in 18 (66.7%). Actionable findings were identified in 14 (77.8%) including 2 with EGFRL858R, 1 with EGFR E19del, and 1 interesting case with EGFR E19del at 45% MAF, EGFR amplification, and an emerging EGFR T790M clone at 0.54% MAF.

Conclusion:
In a series of NSCLC cases, high-sensitivity, high-specificity cfDNA analysis demonstrated the ability to identify somatic tumor alterations, including clinically actionable predictors, in a majority of patients via a simple blood draw, suggesting that this approach can be used for guiding therapeutic decision-making when repeat biopsy is high risk or not possible. Assuming validation, plasma cfDNA analysis may supplant invasive tumor biopsy in the near future.

Background:
As DNA analytical methods have become more sensitive, attempts to develop accurate clinical tests to assess tumor mutation status by means of patient plasma samples are now being pursued. The potential to accurately quantify EGFR mutations in plasma from non-small cell lung cancer (NSCLC) patients would enable more rapid and more frequent analyses to assess disease status; however, the utility of such analyses for clinical purposes has only recently started to be explored.

Methods:
Plasma samples were obtained from 69 NSCLC patients with EGFR-mutated tumors and 21 negative control cases. EGFR mutations in plasma were analyzed by a standardized allele-specific polymerase chain reaction (PCR) test and ultra-deep next generation sequencing (NGS). A semi-quantitative index (SQI) was derived from dilutions of known EGFR mutation copy numbers. Clinical responses were evaluated by RECIST 1.1 criteria and expressed as percent tumor shrinkage.

Results:
The sensitivity and specificity of the PCR test and NGS assay in plasma versus tissue were 72% versus 100%, and 74% versus 100%, respectively. Quantitative indices by the PCR test and NGS were significantly correlated (P<0.001). EGFR testing at baseline and serially at 4–60 days during TKI therapy revealed a progressive decrease in SQI , starting from day 4, in 95% of cases. The rate of SQI decrease correlated with percent tumor shrinkage at 2 months (P<0.0001); at 14 days it was more than 50% in 70% of patients (rapid responders) (Fig.1A-B). In 2 patients with slow response (Fig.1B), an early increase in the circulating levels of the T790M mutation was observed. These patients were defined as early resistant (Fig.1C). No early T790M mutations were seen in plasma samples of rapid responders, suggesting that slow responders are more prone to develop early resistance.

Conclusion:
Quantification of EGFR mutations from plasma with a standardized PCR test is feasible. To our knowledge, this is the first study showing a strong correlation between the EGFR SQI during therapy and clinical response with relevant implications for patient management. With the strong correlation between EGFR SQI in plasma and clinical outcome, this study opens the way to prospectively design clinical trials to confirm these data and evaluate the diagnostic value of this test. Figure 1

Abstract not provided

Background:
Currently, a blood test for lung cancer does not exist. Low-dose spiral computed tomography (CT) has been proposed as an early detection screening tool. However, despite its high sensitivity, the specificity of CT in lung cancer detection is poor. In addition, the necessity for repeated CT scans to determine growth rates over time can expose patients to potentially harmful radiation. Therefore, a minimally-invasive biomarker-based test that could further characterize CT-positive patients based on risk of malignancy would greatly enhance its clinical efficacy.

Methods:
From 2009 through 2013, six hospitals enrolled 1148 patients with lung cancer, 889 blood donors as healthy participants and 36 patients with other lung diseases. The lung cancer associated biomarker panels were identified from the pretreated serum samples and subsequently analyzed in three randomly determined subgroups, the discovery cohort (40 patients with lung cancer, and 45 healthy participants), test cohort (204 patients with lung cancer, and 120 healthy participants), and validation cohort (904 patients with lung cancer, 724 healthy participants, and 36 patients with other lung diseases). Finally the panel of biomarkers were used to predict 12 prospective patients with a suspicious pulmonary nodule by CT images.

Results:
The discovery cohort demonstrated that 4 serum biomarkers (C-reactive protein, prolactin, hepatocyte growth factor, and NY-ESO-1 autoantibody) were significantly higher in patients with lung cancer compared to healthy controls. The 4-biomarker panel was independently investigated in the test cohort and validation cohort. The test characteristics were area under the curve (AUC) of 0.835 (95% CI 0.79-0.873, sensitivity 70.1%, specificity 88.3%) in the test cohort, and 0.818 (95% CI 0.798-0.836, sensitivity 70.0%, specificity 79.6%) in the expanded validation cohort. The 4 biomarkers had no discriminatory power for detecting other benign lung diseases. The performance of the panels in patients with stage I-II lung cancer was AUC of 0.774 (95% CI 0.746-0.801) in the combined test and validation cohorts. Remarkably, analysis model generated by the biomarkers correctly predicted 7 out of 9 prospective patients having lung cancer, and 2 out of 3 patients as benign, which were further verified by the pathologist.

Conclusion:
This study identified four diagnostic biomarkers in serum samples with the potential to distinguish patients with lung cancer from healthy controls. This panel of serum proteins is valuable in suggesting the diagnosis of patients with an indeterminate pulmonary lesion, and potentially in predicting individuals at high risk for lung cancer. Further research is necessary to understand whether these have clinical implications for early detection of lung cancer.

Background:
Early detection represents an important opportunity for decreasing lung cancer mortality. Lung cancer screening with low-dose CT scanning is plagued by a high false-positive rate and non-invasive adjuncts that improve diagnostic accuracy or serve as a pre-screen may be helpful. This study evaluated the performance of a sputum based lung cancer detection (LCD) test that utilizes fluorescence in-situ hybridization (FISH) to detect chromosomal alterations at the 3p22.1 and 10q22.3 loci caused by a cancerous process.

Methods:
At 5 international centers, between March 2012 and July 2014, induced sputum samples were collected from 173 subjects with 8-30 mm solitary pulmonary nodules, where imaging and other subject characteristics mandated biopsy. At least 50 lower respiratory tract cells were required for analysis. The LCD Test, performed at one of 3 reference labs, enabled a combined analysis of sputum cytology and Target-FISH analysis on the same cell using an FDA approved imaging analysis system (BioView Duet™). The LCD test was considered positive if at least 7.5% of the target cells had an abnormal FISH pattern. The results of the LCD were then compared to the clinical pathology. Subjects with an initial non-surgical negative biopsy result were followed for up to 2 years to determine their final diagnosis.

Results:
There were 116 subjects who met the inclusion criteria, had a pathologic diagnosis of lung cancer if the nodule was malignant, and produced adequate sputum for analysis. Seventy-two subjects were diagnosed with lung cancer from the initial biopsy, 7 had definitive negative surgical biopsies, and 37 subjects were classified as indeterminate due to non-surgical negative biopsies. Initial positive concordance was 86.1% (62/72) and initial negative concordance was 71.4% (5/7). From the initial 37 indeterminate negative subjects, additional clinical analyses during the follow up period enabled a definitive classification for 23 subjects: 11 were diagnosed with lung cancer and 12 were reclassified as definitive negative. From this group the LCD test had a positive concordance of 81.8% (9/11) and a negative concordance of 91.7% (11/12). Overall, sensitivity was 85.5% (71/83), specificity was 84.2% (16/19), positive predictive value was 95.9%, and negative predictive value was 57.1%. Fourteen indeterminate negative subjects are still being clinically monitored. The test performance for nodules of 8-20mm was as good as the results for 21-30mm nodules.

Conclusion:
In a cohort of patients with a high risk of lung cancer, the LCD test had a high positive predictive value. A positive LCD test could potentially lead to an earlier intervention in a nodule that might otherwise have been monitored for growth. An adequate cancer resection might then be accomplished by segmental resection rather than lobectomy in smaller lesions. The LCD test may be useful as a decision support tool at critical points in the management of solitary pulmonary nodules detected by screening CT scans in subjects at high risk for lung cancer.

Background:
Lung cancer is conventionally diagnosed by confirmatory tissue biopsy, an invasive procedure that involves waiting time, costs and complications. The development push for a blood based liquid biopsy is a less invasive, more readily acceptable means to expedite the diagnosis and management of cancer. Circulating tumour DNA is promising in this regard as cancer specific genetic mutations are not usually found in the circulation of healthy individuals. The aim of our study is to report the performance of a three gene signature in for the diagnosis of cancer.

Methods:
Pre-operative blood samples were obtained from patients undergoing surgery for known or suspected lung cancer and 1ml aliquots of plasma were extracted from 9ml of EDTA preserved blood. DNA was extracted from the plasma using the QIAamp DNA blood mini kit. High resolution melt analysis was undertaken to identify mutations in hotspots of the TP53, KRAS and EGFR genes in the ctDNA from plasma as well as matching FFPE tissue. A positive test result was defined as a mutation identified in the plasma ctDNA and compared against the reference clinical histopathology report of the resected lung abnormality. Clinical test performance was quantified and reported conventionally using sensitivity and specificity.

Results:
Pre-operative blood was analysed in a blinded manner from 223 patients undergoing surgery at our institution, and the pathology reports were issued blinded to the blood test results. In total, 116 (52%) had primary lung cancer, 64 (29%) had secondary cancer, 6 (3%) had primary thoracic (not lung) cancer and 35 (16%) did not have any evidence of cancer. Of the 186 patients with confirmed cancer, a mutation was identified in the FFPE sections of the primary tumour of 113 (61%) and in the plasma ctDNA in 127 (68%) with substantial agreement of 85% and a kappa statistic of 0.70 (P<0.001). The clinical test performance for the blood based diagnostic signature was a sensitivity of 68% (95% CI 61-75), specificity of 91% (77 to 98), positive predictive value 98% (93-100) and a negative predictive value of 35% (25 to 46) when compared to conventional clinical histopathology reporting of the resected tissue.

Conclusion:
There is substantial agreement between the detection of ctDNA and FFPE tumour tissue mutations. We postulate higher mutation levels detected in the plasma is due to heterogeneity of tumour and FFPE sections in comparison to a global (plasma based ctDNA) estimate of mutation burden. Our results suggest blood based ctDNA analysis of cancer mutations is a specific, non-invasive test for the diagnosis of cancer. A positive test strongly rules in the diagnosis but a negative test does not have sufficient discriminatory ability to exclude the diagnosis of cancer.

Abstract not provided

Background:
Current clinical diagnostic methods lack the specificity in detecting lung cancer patients. The issue is critical for stage I & II patients as there are no available biomarkers to indicate which high-risk patients should undergo adjuvant therapy. There is considerable evidence that microRNA plays a very important role in lung carcinogenesis. We postulated that the expression pattern of multiple microRNAs (miRNAs) could aid clinicians in detecting cancer patients thus reducing the mortality of lung cancer.

Methods:
Differential expressed miRNAs were analyzed by miRNA microarrays in 15 paired non-small-cell lung cancer (NSCLC) tumors and distant normal tissues. The identified miRNAs were further validated by qRT-PCR using snap-frozen lung tissue samples collected from independent 22 patients with NSCLC. Classification analyses of miRNA expression data were performed by the Bayesian Compound Covariate predictor (BCCP). The expression levels of miR-141-5p, miR-301a-3p and miR-1244 were also analyzed by qRT-PCR in serum samples collected from 60 patients with lung cancer and 50 healthy controls.

Results:
A total of 41 miRNAs was identified with significantly elevated levels in patients with lung cancer by profiling microRNA array, of which 12 miRNAs were further validated in the independent sample cohort. Multiplexing analysis with the panel of 12 miRNAs generated the highest discriminatory power in separating NSCLC from normal tissues with an AUC of 0.915 (95% CI = 0.894-1.000; P <0.001). Leave-one-out cross-validation revealed the 85% sensitivity and 95% specificity at a cutoff score of 0.5. In addition, serum miR-1244 was significantly upregulated in an independent trial and could distinguish NSCLC from controls with 77.6% sensitivity and 78.7% specificity.

Conclusion:
Our 12-miRNA classifier might have potential clinical utility in discriminating NSCLC from healthy population.

Background:
Five studies have shown that microRNA levels in whole blood can be used to diagnose lung cancer. We conducted a large bi-institutional study to validate this finding.

Methods:
PAXgene[TM] Blood miRNA System (Qiagen®) was used for peripheral venous blood collection and total RNA isolation for 85 pathologic stage IA-IIIB non-small cell lung cancer cases and 76 clinically-relevant controls who either had a high risk of developing lung cancer because of smoking and age >50 y, or had a benign pulmonary nodule. Cases and controls were accrued at two institutions in the United States, Roswell Park Cancer Institute, Buffalo and University of Pennsylvania, Philadelphia. MiRCURY™ microarrays (Exiqon®) with locked nucleic acid hybridization probes were used to quantify microRNAs in RNA isolates. Quantification was also performed using Taqman™ microRNA reverse transcription (RT)-PCR assays (ABI®) for five microRNAs whose lung cancer-diagnostic biomarker utility had been suggested by the five published studies.

Results:
Cases (n=85) and controls (n=76) were similar for age, gender, race, and blood hemoglobin and leukocyte but not platelet levels (Table 1). Of the 1936 human mature microRNAs detectable with the microarray platform, 586 (30%) were identified as expressed and reliably quantified among the study's subjects. However, none of the microRNAs was differentially expressed between cases and controls (P >0.05 in test using empirical Bayes-moderated t statistics and false discovery rate <5%). In classification analysis using the whole blood microRNA profiles with leave-one-out internal cross-validation, accuracy was 48% and 50% with the support vector machines and top-scoring pair methods, respectively. With RT-PCR assays, cases and controls did not differ for any of the five microRNAs whose biomarker potential had been suggested by previous studies.

Table 1. Characteristics of study groups; *Fisher's exact test for categorical variables, and t test for others; #blood values for 84 cases and 30 controls.

	Cases	Controls	P*
	85	76
Mean age, y (range, SD)	64 (41-83, 8)	61 (45-83, 9)	0.07
%male	49	51	0.87
%white	90	93	0.57
RPCI	42	32	0.43
U. Pennsylvania	43	44
Adenocarcinoma	43
Squamous cell	33
Other non-small cell	9
High-risk control		58
Nodule control		18
Leukocytes (x1000/µl; mean, SD)#	8.2 (2.6)	7.8 (2.1)	0.37
Platelets (x1000/µl; mean, SD)#	291.8 (114.3)	238.2 (50.2)	0.01
Hemoglobin (g/dl; mean, SD)#	13.4 (1.8)	13.9 (1.4)	0.15

Conclusion:
This study suggests that whole blood microRNA expression profiles may not be useful for developing biomarkers for use in non-invasive blood-based assays for generic screening of non-small lung cancer. Further studies are required to examine if whole blood microRNA diagnostic biomarkers may exist for use with specific types of lung cancer or non-cancer control conditions.

Background:
Bronchoscopy is often used for the diagnosis of lung cancer however its sensitivity is imperfect, especially for small and peripheral lesions. Adjunctive methods to improve the sensitivity of cancer detection would reduce the need for more invasive follow-up procedures when bronchoscopy is non-diagnostic. It has previously been shown that gene expression of cytologically-normal bronchial airway epithelial cells is altered in smokers with lung cancer. In this study we evaluated the performance of a bronchial genomic classifier to predict malignancy in an independent cohort of suspect lung cancer patients.

Methods:
A bronchial genomic classifier consisting of the expression of 23 genes measured in the airway epithelium was evaluated in a previously published, independent cohort (n=163) of current and former undergoing bronchoscopy for suspect lung cancer. In cases where bronchoscopy was non-diagnostic for malignancy, the performance of the classifier was evaluated using ROC-AUC, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

Results:
In the test set, bronchoscopy led to a diagnosis in 40 of 78 patients with cancer (sensitivity=51%, 95% CI 40-63%). The combination of the classifier with bronchoscopy improved the sensitivity to 96% (95% CI 89-99%; p <0.001); see Table. The prediction accuracy of the classifier was similar in lesions <3cm, as well as across cancer stage and histology. Among the 123 patients with a non-diagnostic bronchoscopy, 38 were ultimately diagnosed with lung cancer (prevalence of 31%). In this group of patients, the classifier had an AUC of 0.81 (95% CI, 0.73-0.88), accurately identifying 35 of the 38 lung cancer patients (sensitivity=92%; 95% CI, 78-98%), and 45 of 85 patients with benign lesions (specificity=53%; 95% CI, 42-63%). Of the 48 patients with a negative classifier result, 45 were diagnosed with benign lesions (NPV=94%, 95% CI 83-99%).

Table. Performance of bronchoscopy, classifier, and the combined procedures in the test set

Category	Bronchoscopy	Classifier[a]	Combined
Total, N	163	123	163
Lung Cancer, N	78	38	78
Benign Lesion, N	85	85	85
Sens. (95% CI)	51% (40-62%)	92% (78-98%)	96% (89-99%)
Spec. (95% CI)	100% (95-100%)	53% (42-63%)	53% (42-63%)
NPV (95% CI)	69% (60-77%)	94% (83-99%)	94% (83-98%)
PPV (95% CI)	100% (90-100%)	47% (36-58%)	65% (56-73%)

a) The performance of the classifier was evaluated for patients in whom bronchoscopy did not result in a finding of lung cancer (n=123).

Conclusion:
A gene expression classifier measured in bronchial epithelial cells is able to accurately identify those at low risk for lung cancer in patients who have undergone bronchoscopy with non-diagnostic results. Due to the high sensitivity and NPV of the classifier, it could potentially inform clinical decisions regarding the need for further invasive testing for lung cancer in patients whose bronchoscopy is non diagnostic.

Abstract not provided

Background:
The PD-1 and PD-L1 pathway is an immune checkpoint, which protects normal tissues from immune attack by curbing the effector T-cell response but can also prevent anti-tumor immune response. However their role in mesothelioma is not well understood. The present study aimed to understand the PD-1 and PD-L1 expression levels and their interactions in mesothelioma patients.

Methods:
Sections of formalin-fixed, paraffin-embedded pleural and peritoneal mesothelioma tumor samples from patients who were evaluated for various clinical trials at the NCI Center for Cancer Research were tested for PD-L1 expression (Anti-PD-L1 rabbit monoclonal recombinant primary antibody MKP-1B-196-10; Merck-Serono). PD-L1 expression on primary and established mesothelioma cell lines, malignant pleural effusions and ascites of mesothelioma patients were assessed using a commercial anti-PD-L1 antibody and analyzed by flow cytometry. Paired malignant effusion and peripheral blood samples were tested for PD-1 and PD-L1 expression on immune cells. Co-cultures of autologous tumor cells and T cells grown from malignant effusions of a mesothelioma patient were evaluated to understand the PD-1 and PD-L1 interaction.

Results:
Tumor samples from 65 patients included 44 peritoneal and 21 pleural mesotheliomas; 55 with epithelioid histology and 10 of other subtypes (sarcomatoid 2, biphasic 3, uncategorized 5). 41 of 65 (63%) tumors were positive for PD-L1 expression (defined as >5% PD-L1 expression on tumor cells, of any intensity) with levels of expression ranging from 5% to 80% of tumor cells, and intensities from 1+ to 3+. 24 (37%) were negative including 10 with focal staining. A higher proportion of males had tumor PD-L1 expression than females (73% vs. 46%; p=0.04). There was no association between PD-L1 expression and primary site of disease, age, race, histology and distant metastasis. Patients with PD-L1 positive tumors had a numerically inferior overall survival than patients with PD-L1 negative tumors (23.0 months vs.33.3 months; p=0.35). All 6 primary and 4 established mesothelioma cell lines tested showed basal expression of PD-L1. This was enhanced on treatment with IFN-γ. The fraction of cells expressing PD-L1 in malignant effusions ranged from 17 to 43%. Malignant effusions from 2 of 3 patients had high PD-1 expression on both CD4[+] and CD8[+] T cells. In addition, CD8[+] T cells in malignant effusions had significantly higher levels of PD-L1 expression compared to CD8[+] T cells in peripheral blood (7.47±2.75 % T cells versus 1.97±1.22% T cells; p=0.03). Autologous lymphocytes when co-cultured with tumor cells from malignant effusion, recognized tumor cells and induced IFN-γ mediated PD-L1 expression on their surface.

Conclusion:
High PD-L1 expression in mesothelioma patient tumor samples and tumor cells derived from malignant effusions, as well as presence of PD-1[+] T cells in these effusions indicates the prominent role of PD-1/PD-L1 pathway in maintaining an immunosuppressive milieu in mesothelioma. Thus, inhibiting this pathway could be useful therapeutically.

Background:
Whole exome sequencing has revealed key genetic events in several cancer types that have been successfully translated into clinical benefits. These advances are still lacking in malignant mesothelioma (MM), a highly aggressive malignancy with limited effective therapy. Frequent BAP1 mutations occur in a subset of this disease but the full molecular landscape of MM is still poorly characterized.

Methods:
We have therefore conducted whole exome sequencing of tumours from the pleura for 36 cases of MM. DNA from matched blood was available for 7 of the cases and was also sequenced. The variants were identified with GATK tools and annotated with ANNOVAR. Variants were filtered with the following criteria: quality score ≤ 50, present in dbSNP138, 1000 genomes variants and NHLBI ESP 6500 variants. Mutations with deleterious functional consequences predicted by Polyphen-2, SIFT and Mutation Taster tools were confirmed by Sanger sequencing.

Results:
A total of 9,064 variants (3,256 somatic) were identified. We confirmed mutations in genes previously described to be mutated in MM in 5 cases: BAP1 (R227C, Q684X, H141P), NF2 (76_76del, R221X) and TP53 (I195N). In BAP1 wt tumours (6 of the 7 cases with matched blood), we confirmed somatic mutations in 5 genes encoding components of either MAPK or WNT signaling pathways. In addition, we validated somatic mutations in 12 genes across 4 of the 6 cases, many of which are novel in MM and are involved in chromatin modification. We also observed these genes to be mutated in BAP1 wt tumours in the 29 additional unmatched MM cases.

Conclusion:
Thus our data suggests that in addition to BAP1, mutations in genes associated with MAPK, WNT signaling and the chromatin remodeling complex may represent a consistent pattern of molecular alterations in MM.

Background:
The potential of immunotherapy in mesothelioma has recently been demonstrated in multiple (pre)clinical studies. The success of immunotherapy relies on the induction of an anti-tumor immune response which has to overcome the local immunosuppressive environment in established tumors. Tumor-associated macrophages (TAMs) are an important part of the suppressive environment in mesothelioma and reprogramming these TAMs towards a more pro-inflammatory phenotype using a CD40-agonist has shown promising results in multiple solid tumors. Dendritic cell (DC) immunotherapy has been shown to elicit anti-tumor T-cell responses and is currently being studied in mesothelioma patients at our institution. We hypothesize that the combination treatment with a CD40-agonist and DC therapy has synergistic effects and the aim of the current study is to investigate the efficacy of this combinatorial approach.

Methods:
Wildtype Balb/c mice were injected intraperitoneally (i.p.) with the AB1 murine mesothelioma cell line. Different treatment regimens were compared as follows: untreated control group (n=6), monotherapy with CD40-agonist (FGK4.5 monoclonal antibody, n=5), monotherapy with DC immunotherapy (n=5) and combination therapy of DC immunotherapy followed by treatment with the CD40-agonist (n=5). Three days after completion of the treatment regimens, blood was drawn and analyzed using flow cytometry to investigate peripheral immune activation. All mice were monitored and sacrificed when showing signs of severe illness. After sacrifice, tumors are investigated using flow cytometry to determine the local immunological composition.

Results:
Blood analysis revealed that peripheral monocytes of the CD40-agonist group and the combination therapy group showed an increase in expression of MHC-II and PD-L1 compared to the mice in the control group and the DC immunotherapy group. In addition, the combination therapy induced a profound increase in effector CD8 T-cells and proliferating CD8 T-cells compared to the monotherapies. The interim survival analysis at day 40 post tumor cell injection demonstrates a 17% survival of the control group, 80% survival of the monotherapies and 100% survival of the combination therapy. The final survival analysis will be presented at the conference.

Conclusion:
Combination therapy of DC immunotherapy and a CD40-agonistic antibody induces synergistic immune activation in the peripheral blood of mesothelioma-bearing mice compared to the monotherapies. Although the final survival data are awaited, the presented data demonstrate the potential of the combination of cellular immunotherapy and targeting of the local tumor microenvironment in mesothelioma.

Abstract not provided

Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung and peritoneum usually resulting from prior exposure to asbestos. Median overall survival with standard of care (SOC) chemotherapy is only 12 months from diagnosis. This poor prognosis may be attributable at least in part to cancer stem cells (CSCs) that are resistant to chemotherapy and can mediate cancer recurrence and progression. VS-6063 (defactinib) is an oral small molecule that targets cancer stem cells through the inhibition of focal adhesion kinase (FAK). VS-6063 has demonstrated tolerability, target inhibition, and preliminary signs of clinical activity as a single agent and in combination with paclitaxel in Phase 1 clinical trials (Jones et al., J Clin Oncol 29: 2011 (suppl; abstr 3002); Patel et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 5521)). Currently, VS-6063 is being tested in a randomized, double-blind, placebo-controlled trial in malignant pleural mesothelioma immediately following front-line therapy (COMMAND Trial, NCT01870609). In an effort to identify additional mesothelioma patients who may benefit from a CSC targeting agent, we sought to identify compounds that show synergistic anticancer activity with VS-6063. PI3K/mTOR inhibitors were previously demonstrated to show activity in mesothelioma. VS-5584 is a potent oral small molecule that selectively kills CSCs by targeting multiple PI3K isoforms and mTORC1/2 (Kolev et al, Cancer Res; 75:1, 2014). VS-5584 is currently being investigated as a single agent in a Phase 1 clinical trial, (NCT01991938).

Methods:
The synergy between VS-6063 and VS-5584 was demonstrated in vitro using cell viability assays analyzed by CalcuSyn, HSA and Loewe models. CSCs from mesothelioma cell lines were assessed by the Aldefluor+ flow cytometric assays. The anti-tumor activity of the VS-6063 and VS-5584 combination treatment was tested with in vivo mouse mesothelioma xenograft models.

Results:
A dual PI3K/mTOR inhibitor VS-5584 showed synergistic activity with a FAK inhibitor, VS-6063. VS-5584 further enhanced reduction of mesothelioma CSCs by VS-6063 measured by the Aldefluor+ assay in Mero-14 mesothelioma cells. In a 3D matrigel cell viability assay, the combination of VS-6063 and VS-5584 displayed synergistic reduction in cell viability based on multiple combination analysis models. In a MM87 mesothelioma xenograft model in vivo, the single agent treatment with either VS-6063 or VS-5584 was active in inhibiting mesothelioma tumor growth. Combination treatment further enhanced the antitumor efficacy of either agent alone (p <0.0001).

Conclusion:
VS-6063 (defactinib) and VS-5584 exhibit synergistic anticancer activity in preclinical models of mesothelioma. These data provide a strong preclinical rationale for the open dose-escalation Phase I clinical trial of VS-6063 and VS-5584 in patients with relapsed mesothelioma (NCT02372227).

Background:
Malignant pleural mesothelioma (MPM) is a highly aggressive tumour with a high local recurrence rate and often a poor prognosis despite multimodal treatment. We evaluated the prognostic impact of morphological and immunohistochemical changes in sequential biopsies obtained from patients with MPM during disease progression.

Methods:
Tissue microarrays were constructed from paraffin-embedded tissue samples of 36 MPM patients (26 epithelioid, 6 biphasic and 4 sarcomatoid) taken before induction-chemotherapy, during surgery and at the time point of tumour recurrence. Immunohistochemical staining for calretinin, cytokeratin 5/6 (CK5/6) and Wilm’s tumor-1 (WT-1) as well as the biomarkers mesothelin, osteopontin, and fibulin-3 was performed, and staining intensity and percentage of positively stained tumour cells scored semi-quantitatively. The results were correlated with clinico-pathological characteristics of the patients including overall survival (OS). To determine the prognostic value of the markers at the different time points, a multivariate analysis including all factors that were significant in univariate analysis was performed.

Results:
In 28% of patients with epithelioid or biphasic MPM, a transition towards biphasic or sarcomatoid growth pattern during disease progression was observed (Figure 1). This dedifferentiation was associated with significantly decreased immunoreactivity for WT-1 (p=0.03), calretinin (p=0.005), mesothelin (p=0.01) as well as a shorter OS (p=0.04). Figure 1 Overall, patients with epithelioid or biphasic MPM in the diagnostic biopsy had a significantly better OS (29 months; 95% confidence interval (CI): range 27-32 months) in comparison to patients with sarcomatoid MPM (5 months; 95% CI: 3-7 months) (p<0.0005). On multivariate analysis, male gender (p=0.04) and high fibulin-3 (p=0.02) in the pre-chemotherapy samples were found to be associated independently with shorter OS.



Conclusion:
In patients with epithelioid or biphasic MPM, high fibulin-3 expression in pretreatment samples and gender are independent predictors of shorter OS. In up to one third of patients disease progression is accompanied by sarcomatoid differentiation, suggesting that factors such as molecular alterations involved in epithelial-to-mesenchymal transition (EMT) are contributing to disease course and clinical outcome. Alternatively, induction chemotherapy might contribute to this transition by promoting selection and outgrowth of therapy resistant tumor cells. Eventually, the different tumor biology of this subgroup of patients may be taken into account for the consideration of alternative patient handling.

Background:
Growing evidence suggests that nuclear–cytoplasmic transport is frequently dysregulated in cancer cells, and is involved in promoting carcinogenesis, cell survival, drug resistance and tumor progression. In particular, enhanced nuclear export is one mechanism by which malignant cells inactivate tumor suppressor proteins (TSPs). Inhibition of XPO1 (CRM1), the main karyopherin involved in the nuclear export of TSPs, restores nuclear localization and function of TSPs in several preclinical models. Selinexor(KPT-330) is an XPO1 inhibitor being tested clinically in solid tumors and hematological malignancies that showed some activity in patients with thymic epithelial tumors (TETs). Here, we describe the activity of selinexor in preclinical models of TETs.

Methods:
Thymoma (IU-Tab1, T1682), thymic carcinoma (Ty82, T1889, MP57) and immortalized normal thymic epithelial cells (TEC84) treated with selinexor or vehicle were assayed by CellTiter-Glo and flow cytometry. Western blot analysis of nuclear and cytoplasmic protein fractions and immunofluorescence assays were used to study the cellular sublocalization of XPO1 cargoes before and after treatment. The effect of selinexor on cell migration was determined using a wound-healing assay. A selixinor-resistant cell line was generated by growing selinexor-sensitive IU-Tab1 cells at increasing concentrations of the drug. Mutational status and copy number of the XPO1 gene was assessed by Q- PCR and Sanger sequencing.

Results:
All TET cell lines were sensitive to selinexor (IC~50~ 90-250 nM) with the exception of T1682 (thymoma type B), which showed intrinsic drug resistance (IC~50~ > 1000 nM). In the sensitive cell lines, selinexor treatment induced G1 (MP57) or G2 (IU-Tab1, Ty82) cell-cycle arrest at 24 hours, and induced apoptosis 2-5 fold over untreated cells by 72 hours. The cytotoxic effects of selinexor were not observed in immortalized normal TEC84 cells at nanomolar concentrations, and required higher concentrations (IC~50 ~800nM) to induce a cytostatic effect. Drug treatment led to increased nuclear concentrations of several TSPs involved in cell cycle regulation (e.g. p21, p27), genomic stability (p53) and induction of apoptosis (FOXO3a) and also reduced the total cellular expression of the oncogenic protein NF-kB. These results were confirmed with siRNA knockdown of XPO1. In addition,selinexor treatment impaired tumor cell migration and had cytotoxic synergistic effect in combination with doxorubicin or etoposide in T1889 and IU-Tab1 cell lines, increasing nuclear accumulation of the XPO1 cargo protein, Topoisomerase IIα. Furthermore, we demonstrated that selinexor-resistant cell line has similar growth rates to their parental cells, however overexpress XPO1 due to gene amplification, confirming the importance of aberrant XPO1 activity in TET survival.

Conclusion:
Our data show the importance of XPO1 in TETs biology and demonstrate activity of selinexor in preclinical models, further supporting the planned Phase II trial in patients with TETs.

Abstract not provided

Background:
Lung squamous cell carcinoma (SCC) is the second most common histological sub type of lung cancer and accounts for about 30% of all non-small cell lung cancers (NSCLC). We analyzed the NCDB, an oncology outcomes database administered by the American College of Surgeons and the American Cancer Society, to study the epidemiology, patterns of care, outcomes and temporal changes in incidence of SCC.

Methods:
The NCDB was queried from 1998 to 2011 for SCC using ICD-O-3 codes. Temporal changes in incidence were estimated in intervals (1998-1999, 2000-2003, 2004-2007, 2008-2011). The univariate association with covariates between SCC and other subtypes of NSCLC was assessed using Chi-square test or ANOVA. The univariate (UV) and multivariable analysis (MV) with OS were conducted by Cox proportional hazards model and log-rank tests. All statistical analyses were conducted using SAS Version 9.3.

Results:
A total of 435,358 pts with SCC were included in the analysis and accounted for 28% of all NSCLC pts in NCDB. Pt characteristics: median age 70 (18-90 yrs); males 64%; whites 87%; academic centers 27%; metro locations 78%; government insured 72%; Charlson/Deyo comorbidity score (CDS) 0 in 55% and ≥2 in 15%, and stage III/IV- 34/31%. Chemotherapy was used in 39% of pts, radiation in 46% and surgery in 32%. Approximately 19% of the pts did not receive any of the three treatments. Incidence of SCC decreased over time (35%, 28%, 26%, 27%) vs. increasing trend in non-SCC (65%, 72%, 75%, 72%); p<0.001). The trend was similar across all races and sex. SCC was associated with a higher co-comorbidity burden than non-SCC across all stages (CDS 0: 55% vs. 62%; CDS 1: 31% vs. 27%; CDS ≥2: 15% vs. 11%; p<0.001). SCC was associated with inferior 5 yr survival vs. non-SCC in all stages (stage I- 30% vs. 41%, stage II- 16% vs. 21%, stage III- 8.5% vs.10%, stage IV- 1.9% vs. 2.5% respectively; p<0.0001). The 1 yr survival in stage IV SCC is 19.6% vs. 22.2% in non-SCC (p<0.0001). Males had worse survival (HR 1.11 (1.09-1.13; p<0.001). Pts at community centers had worse survival vs. academic centers (HR 1.27 (1.23-1.30; p<0.001). An increasing trend in chemotherapy use was observed (31% in 1998 to 43% in 2011) vs. a decreasing trend in use of radiation (52% in 1998 to 46% in 2011) and surgery (32% in 1998 to 27% in 2011). Chemotherapy was received by 48% of patients with stage IV SCC. Chemotherapy use across other stages: 0/I- 18%, II- 46%, III- 60%. Males were more likely to receive any treatment (OR 1.12 (1.08-1.15); p<0.001). Pts that received any treatment had significantly better 5 year survival than those who did not receive any (20.3% vs. 3.3%, p<0.0001)

Conclusion:
SCC accounted for 28% of all cases of NSCLC in the United States, was associated with higher comorbidities and a significantly worse survival compared to non-SCC of the lung. Chemotherapy was used in only 48% of pts with stage IV SCC.

Background:
Lung cancer is the number one cause of cancer-related death worldwide; with the incidence of non-small cell lung cancer (NSCLC) risen dramatically, the importance of understanding the influence of comorbidities and their treatments takes a great importance. The aim of this study was to investigate the effect of statins and metformin on survival in patients with NSCLC.

Methods:
We reviewed the records of all patients diagnosed with NSCLC at our institution from 2011 to 2013. Demographics, tumor characteristics, comorbidities, statin/ metformin use and survival were analyzed. Cox regression was used for multivariate analysis.

Results:
A total 205 patients were studied. Median age at diagnosis was 65 years (40-91), there were more males than females (56% vs. 44%, p<0.01. 74% (152) were current or former smokers with average 40 pack years (5-60). The Median BMI was 26.5kg/m2 (18-44), ECOG status was 1 (0-4) and serum creatinine of 1.0 (0.4-3.5). Regarding comorbidities: 48% (98) had hypertension, 45% (93) hyperlipidemia, 22% (44) COPD and 19% (39) diabetes mellitus. At diagnosis, 66% (136) of the patients had stage III/IV disease vs. 25% (69) with stage I/II, p<0.0001. Adenocarcinoma was the most common histologic subtype (61%), followed by squamous cell carcinoma (27%). 42% received surgery, 80% systemic chemotherapy and 32% radiation. Median survival was 1520 days (95% CI: 1310-1765). 42% (87) of the patients were taking statins and 13% (27) metformin. About the statin use, 58% of the patients were using statins for 25-48 months, 12% for >48 months, 11% for 13-24 months and 18% for less than 12 months. Female gender (OR: 1.98, p<0.001), age<65 years (OR: 0.89, p<0.01) and statin use (OR: 0.78, p<0.02) were independent predictors of survival by multivariate analysis. Metformin use was not a predictor of survival by univariate or multivariate analysis in this group of patients.

Conclusion:
In our cohort, we observed that almost half of the patients had hypertension and hyperlipidemia with statin use been a significant predictor of survival. Statins are one of the mostly widely prescribed drugs in the US; their proven anti-inflammatory effects may play a role in inhibiting cancer growth. However, the exact mechanisms by which statins inhibit cancer proliferation remains unclear. While other observational studies have looked at statins and risk of developing cancer, we specifically looked at the effect of statins on survival in patients on statin therapy prior to cancer diagnosis. More studies are needed to enhance our understanding of the effect of statins on lung cancer.

Background:
Alterations in glucose metabolism and appetite stimulating hormones have been correlated with inflammation but there is little information on frequency and prognosis in newly diagnosed stage IV non-small cell lung cancer (NSCLC) This study objective was to identify associations of circulating biomarkers of glucose metabolism and inflammation with prognosis in pre-treatment sera from stage IV NSCLC patients selected for platinum doublet based chemotherapy.

Methods:
Pretreatment serum from 118 Pts with frontline stage IV NSCLC were evaluated with the Bio-Plex Pro Human Diabetes Assay panel (adiponectin, adipsin, c-peptide, ghrelin, gastrin inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon, IL-6, insulin, leptin, Plasminogen activator inhibitor-1, resistin, TNFα, vistatin) and HSTCMAG-28SK | MILLIPLEX MAP Human High Sensitivity T Cell Panel - Immunology Multiplex Assay (Fractalkin, GM-CSF, IFNγ, IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17A, IL-21, IL-23, ITAC, macrophage inflammatory protein (MIP)-1α, MIP-1β, MIP-3α, TNFα) on a FlexMAP 3D system (Luminex Corp.). Pts were treated with standard platinum doublets based chemotherapy. Associations of biomarkers with progression free and overall survival (PFS,OS) outcomes were assessed using multivariate Cox PH analyses.

Results:
Most patients had metabolic levels below the prognostic threshold. However, high levels of insulin, GIP, glucagon, visfatin, ghrelin, GLP-1 were significantly associated (p<0.05) with shorter PFS. Low levels of adipisin (deficiency of which is associated with obesity) was associated with shorter PFS (p=.0185). High levels of pro-inflammatory markers: ITAC, GM-CSF, Fratalkine, INF-ϒ, IL-12p70, IL-13, IL17A, IL-4, IL-23, IL8.4, MIP-α, MIP-1 were also associated with poor PFS (p<0.05) (See Table I for more details on select biomarkers) High levels of these endocrine markers (except insulin and GIP) were associated with shorter OS as were ITAC, GMCSF, IL12p70, IL-13, IL4, IL23, IL5 (p<0.05). Table I. Biomarker correlation with progression free survival

Marker	Cutoff-pg/mL	N <	N >	Median PFS <	Median PFS>	Logrank p
Insulin	1004.9	82	36	6.08	4.04	0.026161
Glucagon	361.2	110	8	5.46	1.71	0.010219
Visfatin	8298.3	109	9	5.65	1.45	8.77E-06
Ghrelin	2897.2	104	14	6.02	2.12	0.009423
GLP.1	268.8	109	9	5.65	1.97	0.000618
ITAC	104.7	99	19	5.82	2.96	0.012529
Fractalkine	271.7	97	21	6.08	3.16	0.0067
IL.12.p70.	17.0	109	9	5.65	3.16	0.010631
IL.13	14.9	105	13	5.82	2.76	0.001533
IL.17A	49.4	102	16	5.82	3.65	0.004862
IL.4	66.1	104	14	6.02	2.96	0.000917
IL.8.4	3.0	25	93	12.8	4.8	0.008985

Conclusion:
Imbalances in the glucose metabolism pathway and increased levels of pro-inflammatory circulating markers were uncommon but consistently associated with a poor prognosis in stage IV NSCLC patients early in their treatment cycle. Alterations in these systems have been associated with cancer cachexia and may be targets for intervention in improving prognosis for select patients with NSCLC.

Background:
Previous population-based studies have shown an association between metformin use and improved survival among diabetic patients with lung cancer. We sought to analyze the effect of diabetes and its treatment in terms of survival in Mexican patients with lung cancer treated at a single institution

Methods:
1106 patients were included. Outcomes were compared between patients with (n=186) and without diabetes (n=920). Characteristics associated with antidiabetic treatment and with proper glycemic control (defined as mean plasma glucose <130mg/dL) were examined. Overall survival (OS) among the different patient populations was analyzed using Kaplan-Meier curves and multivariate analysis was used to determine the influence of patient and tumor characteristics on survival

Results:
OS for the entire population was 18.3 months (95% CI 16.1-20.4). There was no difference in OS between diabetic and non-diabetic patients (18.5 vs 16.4 months, p = 0.62). Diabetic patients taking metformin had a superior OS than those taking other antidiabetic treatment (25.6 vs 13.2 months, p = 0.001), and those with proper glycemic control had a better OS than those without proper glycemic control (40.5 vs 13.2 months, p<0.001). Both the use of metformin (HR 0.57 p = 0.017) and proper glycemic control (HR 0.40, p =0.002) were significant protective factors in the diabetic patient population.

Conclusion:
Proper glycemic control and metformin use have a beneficial effect on the survival of patients with diabetes and lung cancer. Studies using metformin in lung cancer should include measures of proper glycemic control as fundamental variables.

Abstract not provided

Background:
Modern systemic treatment options for advanced NSCLC have largely been established from clinical trials (CTs). It is estimated that less than 10% of cancer patients enter a CT, but this subgroup drives oncology practice and impacts treatment decisions for other cancer patients. The advantage of CTs comes from solid internal validity and stringent methodology. Nonetheless, the generalizability of CTs could be questioned due to the high selectivity of eligibility criteria. We investigated clinical trial eligibility in an unselected NSCLC population

Methods:
With ethics approval, a retrospective chart review was performed of patients with de novo advanced NSCLC assessed by medical oncologists at a large academic cancer centre, serving a mixed urban and rural population, between September 2009 and September 2012. Data collected included patient demographics, stage, performance status, histology, treatment details and outcome. Two sets (A and B) of arbitrary eligibility criteria were created using common criteria from phase 3 CTs. These criteria were applied to this cohort to identify the proportions of patient who would hypothetically qualify for CT enrollment. Criteria A required: ECOG 0 or 1, absence of brain metastases, Creatinine < 120 and the absence of second malignancy. Criteria B, allowing broader inclusion, only required ECOG 0-2 and Creatinine < 120. We investigated survival among eligible/ineligible and treated/untreated patients.

Results:
528 patients were included: 55% male; 50% ECOG 0-1; 58% adenocarcinoma, 22% squamous cell; 7% stage IIIB and 93% stage IV. Using the strict CT criteria (A), only 144 (27%) patients were considered eligible. Of those, 79% actually received systemic therapy. From 384 patients who would have been ineligible for the CT, 178 patients (46%) still received systemic therapy. There was a trend to longer median overall survival (mOS) in the eligible treated compared to eligible non-treated patients (11.6 vs 8.1 months p=0.12). mOS was significantly longer in the non-treated eligible cohort compared to the non-treated ineligible cohort (8.1 vs 3.8 months p=0.003). The eligible treated and non-eligible treated had similar mOS ( 11.6 vs 10.2 months, p= 0.10). When less strict eligibility criteria (B) were applied, 343 patients (65%) would have been eligible, of whom 240 patients (70%) actually received systemic therapy. From the remaining ineligible 185 patients, only 51 (28%) received treatment. The mOS was similar in the treated patient whether eligible or ineligible (10.9 vs 10.1 months, p=0.57). As seen in criteria A, significantly longer mOS was observed in the eligible untreated compared to the ineligible untreated ( 4.9 vs 3.5 months p<0.001).

Conclusion:
While clinical trial criteria restrict study entry to the fittest patients, these results suggest that they do not reflect the broader patient population, as many ‘ineligible’ patients received therapy. Extrapolation of treatment paradigms to non-trial eligible populations is common, and may be reasonable based on these results. We observed similar survival among treated patients, whether trial eligible or not. This suggests that clinical judgement is more important than trial eligibility. In order to broaden trial participation, we could hypothesize that trial eligibility criteria could be relaxed.

Background:
CNS metastases are common in NSCLC, yet clinical trials of new drugs in NSCLC have widely varying inclusion and exclusion criteria in relation to CNS disease. CNS disease that has received local therapy may be dormant, confounding any subsequent drug benefit, whereas untreated CNS disease may reduce PFS if CNS and systemic drug exposure differs. Recently, RANO guidelines propose explicitly explored activity in CNS disease within solid tumor drug trials. The true extent of variation in CNS related enrollment criteria in NSCLC clinical trials has not been documented before.

Methods:
ClinicalTrials.gov was interrogated on September 11, 2014 looking for interventional drug trials including advanced NSCLC. The following characteristics were extracted: 1) trial phase; 2) experimental arm therapy (chemotherapy, targeted therapy, immunotherapy, anti-angiogenic); 3) location (US, International only, US + International); 4) sponsor (Industry, University/IIT, Cooperative Group, NCI); 5) CNS disease allowance (strict exclusion, allowed after local treatment (surgery/radiation), unrestricted/untreated disease allowed). Industry sponsorship was divided into ‘large pharmaceutical’, (top decile by number of sponsored trials) and ‘small pharmaceutical’ (lower 9 deciles). Exclusion of CNS metastasis was treated as a binary variable and grouped as ‘strict exclusion’ vs. ‘allowed CNS metastasis’ (‘allowed with treatment’ and ‘allowed untreated’). Univariable and multivariable logistic regression models were fit to test the association between exclusion of CNS metastasis and trial characteristics. Statistical significance was set at 0.05 with no adjustment for multiple testing.

Results:
Of 735 trials involving NSCLC, 325 (44%) were excluded from analysis mostly because of allowance of early stage NSCLC (50%, n=164), or no active therapy inclusion (45%, n=146). In the remaining 406 trials, patients with CNS metastases were excluded in 58 (14%), allowed after local treatment in 165 (41%), and allowed with no prior treatment in 104 (26%). CNS criteria were not referenced in the available information in 79 (19%) trials which were excluded from further analysis. On univariable analysis, the odds of CNS metastasis exclusion on trial were significantly lower in trials with vs. without targeted therapy (OR 0.44, 95% CI: 0.25-0.78, p=0.005) and significantly higher in trials with vs. without immunotherapy (OR 2.13, 95% CI: 1.06-4.28, p=0.04). No other univariable associations were significant. In multivariable analysis, after adjustment for all other factors, only trials located at international only vs. US only sites had greater odds of exclusion of CNS metastasis (OR 1.64, 95% CI 0.84-3.22; p=0.03).

Conclusion:
Although univariable analysis suggests class of agent may influence trial design, in multivariable analysis trial location was the only variable associated with strict exclusion of CNS metastases. This raises the possibility of exclusion based on historical/cultural rather than scientific factors. With 18% of trials (58/327) excluding all CNS disease and 50% (165/327) only allowing CNS disease if previously treated, less than a third of NSCLC trials permit unequivocal assessment of CNS activity (104/327). Given the high frequency of CNS disease in NSCLC, sponsors should consider consciously tailoring trial designs to more explicitly explore efficacy in this patient population.

Background:
The American Society of Clinical Oncology (ASCO) recently developed a set of recommended targets for clinically meaningful outcomes to encourage patients, advocates and investigators to expect more of clinical trials in the future and to encourage investigators to design trials and select agents that have the most promise. A systematic literature review was conducted to identify where and how research has successfully met the bar for meaningful improvements in NSCLC patient survival.

Methods:
A systematic search strategy was implemented in MedLine and EMBASE to identify randomized phase III trials reporting overall survival (OS) outcomes from 1974-present. Eligible studies were those that reported OS data in terms of a hazard ratio (HR) or median OS. Patients in the eligible randomized trials were NSCLC patients treated in the first (1L) or post-first line (2L+) setting. Data were extracted related to study population, histology, interventions, and survival from trials of patients with advanced or metastatic disease. All eligibility determinations and extracted data were reviewed by two researchers for accuracy.

Results:
The search strategy identified 2051 articles that were reviewed for eligibility. Of these, 245 were eligible for inclusion. 198 (80.8%) studied 1L, 45 (18.4%) 2L+, and 2 investigated both lines. Of all articles, 51 (20.8%) found significant improvement in survival (Figure 1). Of these, 45 (88.2%) were 1L (41 studies). 14/41 (34.1%) were terminated early or had major protocol changes during study enrollment, and 5/41 (12.2%) reported inconsistent outcomes. In significant 1L studies, the median OS improvement ranged from 0.3-7.0m and HRs ranged from 0.35 to 0.87. The 4 2L+ positive studies, OS improvement ranged from 1.4-2.8m and HRs from 0.70-0.86. Of all 198 1L publications, 12 studies met the significant HR <0.80 bar and an additional 12 studies reported statistically significant gains of ≥2.5m OS. Figure 1. Publications reporting significant improvement in survival Figure 1



Conclusion:
There is a need to improve survival outcomes for patients in NSCLC. In 1L, few studies would have met the ASCO target. Only four 2L+ trials were identified with significant improvements in NSCLC. The results of this systematic literature review inform the interpretation of research and the new bar recommended for meaningful outcomes.

Background:
There are general standards for common clinical trial data elements submitted to US Food and Drug Administration (FDA) in a new drug application (NDA) or biologic license agreement (BLA). There is, however, considerable heterogeneity in the structure of data elements that are unique to a particular therapeutic area. As part of an effort organized by Coalition for Accelerating Standards and Therapies (CFAST), we developed specifications for efficacy data standardization in lung cancer.

Methods:
Using FDA guidance documents, NDA and BLA reviews, sample case report forms, and clinical trial datasets, we identified data elements in lung cancer clinical trials that are essential in evaluating the efficacy of new drugs and biologics. We constructed a concept map outlining the data elements and specifying their relational structure.

Results:
Data elements were captured under two main categories: efficacy endpoints (Figure 1) and covariates (Figure 2). Efficacy endpoints consist of overall survival, progression-free survival, objective response rate, duration of response, and disease-free survival. All lesions are assigned an organ-specific code. Data on tumor kinetics are captured as continuous variables supporting precise estimation of response while capturing all the requirements of Response Evaluation Criteria in Solid Tumors, version 1.1. Covariates were divided into disease and patient characteristics. Disease characteristics include specifications on molecular, immunohistochemical, and histological classification of tumors and detailed staging variables. Molecular definitions follow established nomenclature and include information on mutation subtypes as indicated. Patient characteristics include information on prior therapy, race and ethnicity. Figure 1 Figure 2





Conclusion:
The data elements we have identified (Figures 1 and 2) include concepts not adequately captured in current data standards and highlight important regulatory needs for the efficacy evaluation of new drugs and biologics in lung cancer. These specifications will be integrated with CFAST’s efforts to promote the development of lung cancer-specific data standards.

Abstract not provided

Background:
In collaboration with the FDA, the Patient-Reported Outcome (PRO) Consortium’s Non-Small Cell Lung Cancer (NSCLC) Working Group (WG) has completed the initial development of a new PRO measure to assess symptom-related treatment benefit in clinical trials of advanced NSCLC to support labeling claims.

Methods:
Symptoms relevant to NSCLC patients were identified from the literature. This was followed by concept elicitation interviews conducted with patients at six US sites. Interview transcripts were coded using Atlas.ti software and concepts were grouped by similar content and subsequently reviewed by the NSCLC WG members and an expert panel in order to identify the symptoms most relevant for assessing treatment benefit. Preliminary items were generated and combined into a draft measure for cognitive testing with NSCLC patients for both item refinement and for assessing measurement equivalence between the original paper format and an electronic PRO (ePRO) data collection format (i.e., tablet).

Results:
For concept elicitation, the 51 patients interviewed had a mean age of 64.9 years [range 46-86], 51% were female, and 75% were white (non-Hispanic). Current NSCLC staging was: Stage I (12%), III (37%), and IV (51%). A total of 19 (37%) were treatment-naïve, 18 (35%) had received first-line treatment only, and 14 (27%) had received second- or third-line treatment. The most commonly expressed symptom was fatigue, described by patients as tiredness, lack of energy, tiring easily, and weakness. Other symptom concepts expressed included general pain, chest pain, cough, shortness of breath, difficulty breathing, appetite change, and coughing up blood. Items were drafted to assess either symptom frequency or severity for nine distinct symptoms using a 7-day recall period. Cognitive interviews were conducted in 3 waves to support iterative refinement. 20 additional NSCLC patients participated [mean age 65.2 years (range 44-83); 40% female; 75% white (non-Hispanic); 50% Stage III and 50% Stage IV]. During cognitive interviews, an 11-point numeric rating scale (NRS) and a 5-point verbal rating scale (VRS) were tested. Results indicated the 5-point VRS was better understood than the 11-point NRS. Further item refinement resulted in a 7-item measure covering pain (2 items: pain in chest, pain elsewhere), cough, shortness of breath, fatigue (2 items: energy, tiredness), and appetite. Patients reported no differences between tablet and paper data collection formats in regard to how they would interpret and respond to the items.

Conclusion:
NSCLC symptoms elicited from patients, across varied disease stages and treatments, were concordant with the pathophysiology of NSCLC. A new symptom-based PRO measure is being developed in accordance with the FDA’s PRO Guidance. The content is supported by existing literature, patient-reported experiences, and expert opinion. The draft measure (i.e., Non-Small Cell Lung Cancer Symptom Assessment Questionnaire [NSCLC-SAQ]) has been programmed onto an ePRO tablet for quantitative testing. Once complete, the NSCLC-SAQ and supporting evidence will be submitted to the FDA for its qualification as an efficacy endpoint measure to quantify treatment benefit for product evaluation and labeling.

Background:
The evolution of targeted therapy in non-small cell lung cancer (NSCLC) has led to growing complexity of clinical research and a heightened expectation of clinical benefit for participants. Clinical trials in NSCLC increasingly require mandatory tumour samples or research biopsies, both potential barriers for trial participation. We assessed the impact of performing research biopsies in advanced NSCLC on clinical trial enrollment.

Methods:
We conducted a retrospective chart review of patients with advanced NSCLC evaluated for systemic therapy clinical trials at the Princess Margaret Cancer Center from January 2007 to March 2015.

Results:
Of 55 clinical trials reviewed, 38 required tumor samples for enrolment. Six mandated fresh tumor biopsies, whereas archival samples were permitted for 32 trials. All studies were linked to investigational therapy except one trial of molecular profiling not linked to an investigational treatment. Confirmation of a pre-specified biomarker was required in 23 trials in order to receive investigational treatment. Trial participation was offered to 640 patients at 940 unique study encounters, with some patients enrolling in multiple trials. Of 549 encounters where study treatment was offered, 60% proceeded to receive study treatment. Those considering trials without mandatory tissue requirements were more likely to proceed to study enrolment than those considering trials with these requirements (83% vs. 55%, p<0.0001). Those considering trials permitting use of archival tissue were more likely to begin study treatment than those considering trials mandating fresh research biopsies (59% vs. 38%, p=0.0007). For trials requiring current tumour samples, 127 research biopsies were performed. Participants proceeded to study treatment in 51% of these encounters. Study treatment was not offered for the remaining encounters due to lack of the pre-specified biomarker (28%), insufficient biopsy tissue (6%) or non-biopsy related exclusion criteria (15%). Among all 549 trial encounters, the most common barriers to trial enrollment included lack of the pre-specified biomarker (35%), withdrawal of consent (20%), other study exclusion criteria (16%), insufficient biopsy tissue (10%), deteriorating clinical status (10%) and death (5%). Of 391 encounters for the molecular profiling trial, 72% successfully completed molecular profiling. Twenty-two percent had insufficient tissue for analysis and 3% died prior to completion of molecular profiling.

Conclusion:
With the evolution of personalized medicine, a growing number of NSCLC trials require tumour tissue for treatment eligibility. This has emerged as a significant barrier to clinical trial enrollment. Potential solutions include routine tissue banking at diagnosis, facilitating use of available diagnostic samples (e.g. fine needle aspirates) for trials, development of circulating DNA assays for trials, and more resources for timely tissue acquisition.

Background:
Clinical management of lung cancer and personalized cancer therapy have undergone major advances and paradigm shifts in recent years. Repeat tumor biopsy (RTB) at disease progression is not only used for diagnostic confirmation in lung cancer but also has recently been increasingly adopted to profile tumor biomarkers and identify drug resistance mechanisms. However, information on safety and clinical consensus on the use of RTB remain lacking.

Methods:
The aim of this study is to review RTB patterns and safety in advanced lung cancer patients at Cleveland Clinic and its impact on treatment (Rx) decisions. Patients who were diagnosed and underwent RTB for suspected progressive disease between 2007-2013 were included in this retrospective study. Statistical analysis is primarily descriptive.

Results:
The study involved a total of 184 (56% male) patients. Median age at diagnosis was 65Y (21-87). 100 (54%) were treated initially with single modality (Surgery = 41; Chemo = 33; Radiation = 17; targeted therapy = 9) and 83 (45%) with multimodality Rx (2-modality = 57, 3-modality = 26), 1 (1%) unknown. Number of RTB per patient: 1 in 66.3% (n=122), 2 in 20.1% (n=37), 3 in 11.4% (n=21), and 4 in 2.2% (n = 4). The most common procedure employed at 1st RTB was bronchoscopy (44.6%, n = 82), followed by CT-guided biopsy (bx) (20.7 %, n=38), surgery (10.3%, n=19), excision bx (8.2%, n=15), fine needle aspiration of skin & lymph node (LN) (7.6%, n=14), ultrasound guided bx (5.9%, n=11) & others (2.7%, n=5). Lung was the most commonly rebiopsied site (46%) followed by LN (15%). Procedure-related complications were reported in 13 of 181 (7.2%) pts at 1st RTB (data missing in 3 pts), 3 of 61 (4.9%) at 2nd RTB, 1 of 25(4%) at 3rd RTB, and 0 of 4 (0%) at 4th RTB. The 17 (6.2%) complications are shown in the table below. Histologic change was seen in 13 cases, including adeno-to-squamous carcinoma (at erlotinib resistance) and vice-versa, and non-small cell to small cell histology. The T790M-EGFR mutation was noted in 6 cases, the PIK3CA mutation in 1, and a change in ALK translocation status in 3. Medical decision-making was impacted in 16% of cases. Further molecular and genomic analysis of selected cases is in progress.

RTB Complications

Complications	N=17 (%)
Bleeding without hemodynamic compromise	6 (35)
Bleeding requiring transfusion	1 (6)
Pneumothorax	5 (29)
Hemodynamic instability after premedication	1 (6)
Cerebral salt wasting	1 (6)
Tracheaoesophageal fistula	1 (6)
Severe cough	1 (6)
Incomplete procedure	1 (6)
Deaths	0 (0)

Conclusion:
Our study results show that RTB can be safely performed in lung cancer patients using standard techniques and can impact lung cancer diagnosis and Rx decision-making.

Background:
The National Lung Matrix Trial is a flagship trial in the United Kingdom being the first to combine the development of a technology platform that screens for multiple genetic aberrations in tumours with testing of multiple novel genetic-marker-directed drugs. The trial is focused on patients with advanced non-small cell lung cancer and currently includes 8 different drugs and 23 different drug-biomarker combinations. The aim of statistical analysis is to determine whether there is sufficient signal of activity in any drug-biomarker combination to warrant further investigation and this paper evaluates the novel statistical design that has been implemented.

Methods:
The primary outcome measure representing signal of activity is best objective response rate (ORR) in most cases and progression-free survival (PFS) in others. Each drug-biomarker combination could be considered as a single arm phase II trial and could have been designed using standard statistical approaches such as Simon’s two stage design. However, a Bayesian adaptive design was chosen because it gives a more realistic approach to decision-making in this complex setting. It has flexibility to make conclusions without fixing the exact sample size which will be important with the uncertainty around the prevalence of each biomarker. The design allows early stopping of recruitment to any drug-biomarker combinations that do not show sufficient promise at an interim analysis to warrant continuation. It also allows, when appropriate, for information about the primary outcome measure to be shared across different biomarker cohorts within any single drug to aid decision-making. Decision-making is based on the posterior probability distribution for the primary outcome measure, given the observed data and any prior knowledge, calculated using bayesian conjugate analysis. For ORR, the critical threshold which defines a signal of activity is 30% for single drugs and 40% for combinations and for PFS the critical threshold is median 3 months. The interim and final sample sizes were selected to ensure the design achieved pre-defined desirable operating characteristics.

Results:
For both ORR and PFS as primary outcomes, sample sizes of 15 and 30 patients per drug-biomarker cohort for interim and final analyses respectively were selected as giving the required operating characteristics. Simulations of trials for single drugs with ORR as the primary outcome showed that this would ensure a high probability (82%) of correctly stopping early when the true ORR was only 10% and a high probability (90%) of correctly recommending further investigation when the true ORR was as high as 40%. Operating characteristics for the combination drug arms were similar. Operating characteristics for trial arms with PFS as the primary outcome are dependent on the recruitment rate and give high probabilities (>95%) of stopping early when the true median PFS is only 1 month and high probabilities (>80%) of recommending further investigation when the true median PFS is as high as 4 months.

Conclusion:
The Bayesian adaptive design with 15 and 30 patients per drug-biomarker cohort for interim and final analyses respectively gives a flexible, efficient design with good operating characteristics to investigate multiple genetic-marker-directed drugs within a single phase II trial.

Abstract not provided

Background:
Reovirus is a naturally occurring virus which preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. Cells that express high levels of EGFR are also susceptible to reovirus infection. In preclinical studies, reovirus induces host immunity and cell cycle arrest, acting synergistically with standard cytotoxic agents. Its adverse effects are mild to moderate flu-like symptoms. We have hypothesized those patients with EGFR-mutated, EGFR-amplified, or Kras-mutated NSCLC through a common downstream activated Ras pathway should be susceptible to treatment with reovirus

Methods:
We designed a Fleming, single-arm, phase II study to evaluate the objective response rate (CR + PR RECIST, or >40% PET SUV decrease) of reovirus in combination with paclitaxel-carboplatin as first-line therapy in patients with metastatic NSCLC. Secondary endpoints included progression free and overall survival. Eligible patients had ECOG PS 0-2, adequate organ function, no prior systemic chemotherapy for metastatic disease, and tumors with the specified genotype, as per CLIA certified testing. Adjuvant chemotherapy, or erlotinib/gefitinib for pts with EGFR mutant tumors was permitted.

Results:
Thirty-seven patients were enrolled. Molecular tumor demographics included 20 pts with Kras mutations; 10 with EGFR amplification alone; 3 patients with EGFR mutations and four patients with BRAF V600E mutations. Overall, 258 cycles (median 4, range 1-47) were administered. Initial doses used were C AUC 6 on day 1, and P 200 mg/m[2],on day 1 of each 21-day cycle. Due to unacceptable toxicities (grade 3 diarrhea and febrile neutropenia [1 each]) in the first two patients, doses were reduced to P 175 mg/m-m[2] and C AUC 5.. Common toxicities considered at least possibly related to the therapy included fatigue (30 pts); diarrhea (21 pts); nausea (19 pts); arthralgia-myalgia (15 pts); and anorexia (9 pts). Grade 3-4 adverse events included neutropenia (7 Gr3, 1 Gr4), anemia (2 Gr3), fatigue (9 Gr3), diarrhea (3 Gr3), nausea/vomiting (3 Gr3) and a single case of sepsis. Response evaluation showed 11 PR (5 Kras mutant), 20 SD, 4 PD and 2 NE patients by RECIST (ORR: 31%, 90% one-sided lower CI: 21%). Four of the SD patients had >40% PET SUV reductions after two cycles. Three patients opted to switch to pemetrexed maintenance after 4 cycles without disease progression or moderate/severe toxicity. Median PFS, OS and 12 month overall survival rates were: 4 months (95% CI: 2.9-6.1), 13.1 months (95% CI: 9.2-21.6) and 57% (95% CI: 39-72%), respectively. Seven patients are alive after a median follow up of 34.2 months (range: 26.9-71.5), including two patients with no evidence of disease progression to date (50 and 37 months).

Conclusion:
Oncolytic reovirus administration in combination with paclitaxel and carboplatin was well tolerated. The RECIST response rate (11/35 [31%]; 28% of Kras mutants)(15/35; 43% if PET is considered) is not conclusive, nor excludes additional benefit of the reovirus to chemotherapy. However, the number of patients surviving longer than 2 years (11; 30%) is substantial, suggesting either effect of second/third line post paclitaxel/carboplatin/reolysin treatment or perhaps the triggering of an immune response following tumor reovirus infiltration. The latter concept merits further investigation.

Background:
KRAS mutations, which occur in approximately 30% of lung adenocarcinoma cases, represent a major unmet clinical need in thoracic oncology. Preclinical studies have demonstrated that KRAS mutant NSCLC cell lines and xenografts with additional alterations in either p53 or INK4a/Arf (CDKN2A) are sensitive to FAK inhibition. Defactinib (VS-6063) is a selective oral inhibitor of FAK. This trial examined the effect of FAK inhibition in patients with KRAS mutant NSCLC and various permutations of p53 and CDKN2A alterations.

Methods:
This multi-center, non-randomized, open-label, multi-cohort trial enrolled patients with advanced KRAS mutant NSCLC who had received at least one prior (platinum-based chemotherapy doublet) line of therapy. The primary endpoint was progression-free survival (PFS) at 12 weeks. Patients were enrolled into one of four cohorts defined by INK4a/Arf and p53 status. In all cohorts, patients received defactinib 400 mg orally BID until disease progression.

Results:
Fifty-three patients with KRAS mutant NSCLC were enrolled across 9 US sites as of the data cut-off date (13-Mar-2015). Forty-seven patients were enrolled to one of the four molecularly defined cohorts. The median age was 62 years (range 33-80); 48% were female. The median number of prior lines of therapy was 3 (range 1-8) 15 (28%) pts met the 12 week PFS endpoint, with one patient achieving a PR. Median PFS was 46 days (range 12-205 days). Eight patients remained on study as of the data cut-off date. Clinical efficacy did not correlate with secondary mutation status across this KRAS mutant population. Adverse events considered at least possibly related to defactinib were experienced by 35 pts (76%). The majority of these were grade 1 or 2. 11 patients (24%) experienced at least possibly related grade 3-5 events, including 2 grade 5 respiratory failure events. Underlying disease was a confounding factor in many pts. The most commonly reported treatment emergent adverse events of any grade were fatigue (24%) and increased bilirubin (24%).

Conclusion:
In pretreated pts with KRAS mutant NSCLC defactinib demonstrates promising clinical activity with disease control rates comparable to other molecularly targeted agents for this pt population. Defactinib was generally well tolerated. Further development is warranted. Clinical trial: NCT01778803.

Background:
Tobacco-related non-small cell lung cancer (NSCLC) is associated with reduced survival and greater genomic instability. Veliparib (V) is a PARP inhibitor that augments platinum-induced DNA damage in preclinical studies, and a recent Phase 2 trial of advanced NSCLC trended to improved survival (HR 0.80; CI 0.54–1.18) when V was added to carboplatin (C) and paclitaxel (P). Here we report outcomes based on smoking status from this randomized Phase 2 study of CP with either V or placebo in advanced NSCLC.

Methods:
Patients with previously untreated advanced/metastatic NSCLC were randomized 2:1 to CP with either V at 120mg BID or placebo (randomization stratified by histology and smoking history). Cotinine was measured in patients’ plasma samples as an index of recent tobacco use.

Results:
Of 158 patients, 68% were male, and 49% had squamous NSCLC. At study entry, 60% pts were self-reported current smokers, 27% former smokers, and 13% never smoked. There were no significant differences in veliparib pharmacokinetic parameters between cotinine-high and low. Grade 3/4 AEs were elevated in current-smokers treated with VCP vs CP (66% vs. 40%, p=0.026); all-grade AEs and SAEs were similar between the two groups. The most common AEs in current-smokers were neutropenia (41% VCP; 27% CP), alopecia (36%; 33%), and anemia (31%; 40%). Figure 1 A sensitivity analysis of heavy vs light-smokers (≥ vs <39 pack-years, current or former smokers) showed advantage of veliparib in heavy-smokers: median PFS [HR(95% CI)] for VCP/CP was 7.0 vs 3.5 [0.43(0.20–0.94)] for heavy-smokers and 4.4 vs 4.2 [0.97(0.49–1.92)] for light-smokers; median OS was 12.6 vs 8.8 [0.52 (0.27–1.02)] for heavy-smokers and 9.9 vs 8.8 [0.92(0.53–1.61)] for light-smokers. A cotinine sensitivity analysis found that outcomes in cotinine-high were similar to current-smokers: PFS, cotinine-high HR was 0.38 (0.19–0.73) and cotinine-low was 0.97 (0.51–1.87); OS, cotinine-high HR was 0.52 (0.29–0.92) and cotinine-low was 1.07 (0.63–1.81). In univariate analyses assessing the influence of baseline characteristics and treatment on outcomes, smoking status and treatment had a significant interaction (p=0.0301 PFS, p=0.0118 OS). Additionally, multivariate analysis including all factors also identified current smoking as predictive of improved outcomes with VCP.



Conclusion:
Smoking status was a strong predictor of efficacy for veliparib-chemotherapy combination in advanced NSCLC. No differences in pharmacokinetics of V were seen based on plasma cotinine; toxicity of VCP was acceptable regardless of smoking history. A Phase 3 study has been initiated in patients with smoking history (M14-359).

Background:
Cabozantinib (C) is a small molecule inhibitor of multiple receptor tyrosine kinases, including MET, VEGFR2 & RET. MET is involved in tumor differentiation & VEGFR2 is a mediator of angiogenesis. Erlotinib (E) is FDA approved for the treatment of NSCLC.

Methods:
The primary objective of this randomized phase 2 study was to compare progression-free survival (PFS) of pts treated with E vs. C, & E vs E+C; each comparison had 91% power to detect a PFS hazard ratio (HR) of 0.5 with a 1-sided 0.10-level test stratified on prior number of therapies & ECOG PS. Secondary objectives included overall survival (OS), RECIST 1.1 response & CTCAE v4 toxicity. Pts were selected with previously treated (1-2 regimens) metastatic non-squamous EGFR wt NSCLC. Submission of archival tissue for central MET IHC testing was required. Oral daily dosing was: E-150 mg; C-60 mg; E+C-150 mg E, 40 mg C. Imaging was performed every 8 weeks. Pts optionally crossed over to E+C following progression on E or C.

Results:
125 pts were enrolled, of which 115 were eligible & treated (E, n=39; C, n=39; E+C, n=37). Pt characteristics were balanced between arms except for lower rate of brain mets history on E (p=0.02). Median follow up is 8.5 m. Compared with E (median 1.9 m), PFS was significantly improved on C (3.9 m, HR 0.33, p=0.0002, 80% CI 0.22-0.49) & E+C (4.1 m, HR 0.31, p=0.0002, 80% CI 0.21-0.46). Similarly, compared with E (median 4.0 m), OS was significantly improved on C (HR 0.52, p=0.02) & E+C arm HR 0.50, p=0.02). Grade 3-4 treatment-related hypertension & mucositis were higher on C and grade 3-4 diarrhea was higher on E+C. Overall worst grade toxicities were also significantly higher on C and E+C. MET IHC results were available on 88 patients from the primary analysis & 85% were positive (1-3+ membrane or cytoplasm staining with MET4 antibody). There was no correlation between MET status and PFS.

Conclusion:
C & C+E significantly improved PFS over E alone in pts with EGFR wt NSCLC. Cabozantinib-based regimens are promising for further investigation in this patient population. Funded by ECOG-ACRIN and NCI Contract No. HHSN261200800001E.

Abstract not provided

Background:
EGFR exon 20 insertions (ins20) represent a rare subtype (4%) of EGFR mutations and are refractory to EGFR-specific tyrosine kinase inhibitors (TKIs). No effective targeted therapies exist for patients (pts) with ins20; median PFS on the irreversible EGFR TKI Afatinib is 2.8 months (mos). Based on a durable RECIST partial response (PR) to AUY922, a Heat Shock Protein 90 (Hsp90) inhibitor, observed in an EGFR ins20 patient in a previous study (NCT01124864), we designed a phase II investigator-initiated trial to assess the activity of AUY922 in NSCLC pts with EGFR ins20. Since pts with these mutations are rare, we identified other international investigators who have treated ins20 patients with AUY922. Here, we present the results of a pooled international experience of 21 patients with EGFR ins20 treated with AUY922 in the United States, Taiwan and the Netherlands.

Methods:
A total of 21 patients with EGFR in20 are included in this analysis. 14 were treated on a single-arm, multi-center, open-label study of AUY922 in advanced NSCLC pts with EGFR ins20 mutations in the US (NCT01854034). Five were treated on a multicenter Taiwanese trial of AUY922 across a variety of molecular NSCLC subtypes (NCT01922583) and two were treated on a compassionate-use basis in the Netherlands. The starting dose of AUY922 was 70mg/m2 IV weekly for all patients.

Results:
21 pts, including 14 females and 7 males, average age 55 (range, 27-75) were included in this analysis. The median number of prior therapies was 2 (range, 1-6.) 6 pts received a prior EGFR TKI; none responded to TKI monotherapy. The most common AUY922-related toxicities were grade 1-2 visual changes (18/21; 86%) diarrhea (18/21; 86%) and fatigue (15/21; 71%). The only treatment-related grade 3 toxicities was hypertension (2/21; 1%) and AST elevation (1/21; 0.5%). There was one death on study, related to pre-existing comorbidity/unrelated to AUY922. Among the 21 patients treated, 5 achieved a partial response by RECIST 1.1 (ORR 24%) (Figure 1.) The median PFS estimate is 3.9 mos (95% CI, 2.9 to 10.7.) 6 patients remain on treatment at the time of abstract submission. Updated results and correlation with specific ins20 mutations will be presented. Figure 1



Conclusion:
This international experience suggests that AUY922 may be an active therapy for advanced NSCLC pts with EGFR ins20 mutations with an ORR 24% and median PFS 3.9 mo. AUY922 is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of AUY922 in this population is warranted.

Background:
To avoid uncontrolled off-label use and allow for a nationwide safe access to crizotinib (crz) for patients (pts) with an ALK, MET or ROS1 positive (+) tumor, the French National Cancer Institute (INCa) launched the AcSé program, funding both access to tumor molecular diagnosis and an exploratory multi-tumor 2-stage design phase II trial. We report the preliminary results of the ROS1+ NSCLC cohort.

Methods:
ROS1 status was assessed in 28 regional INCa molecular genetic centers by break-apart FISH assays in tumor samples showing an IHC score of ≥1+. Pts with ROS1 rearrangements, progressing after at least one standard treatment (including a platinum-based doublet, unless pts were considered as unfit for chemotherapy) were proposed to receive crz 250 mg BID. Responses were centrally assessed using RECIST v1.1. The objective response rate (ORR) and disease control rate (DCR) were assessed every 8 weeks.

Results:
From Aug. 5, 2013 to Mar. 1, 2015, 39 pts with ROS1+ NSCLC were enrolled. 37 pts had received crz, leading to 37 pts with clinical information. Median age: 62 years (range 33–81), 70% females, 95% non-squamous histology, and 94% metastatic disease at study entry. Median number of prior treatments: 2 (range 1 –7). Twenty four pts were still on treatment at the cut-off date, 13 have stopped crz (8 PD, 3 adverse events (AEs), 2 deaths). Among the 27 pts evaluable for response at 8 weeks, we observed 16 PR, 7 SD and 4 PD, leading to ORR=59% [95% CI:39-78], and DCR=85% [66-96]. DCR at 6 months was 57% (disease control was achieved in 12/21 evaluable pts). Crz was well tolerated with only 4 grade ≥3 (1 AE + 3 SAEs) and 9 grade 1-2 SAEs. Most common AEs, mainly grade 1, were visual disorders (54% of pts), peripheral edema (51%), diarrhea (48%), nausea (46%), and elevated transaminases (43%).

Conclusion:
Crz was well tolerated and achieved a robust treatment response rate in ROS1+ NSCLC. These results underline the interest of integrating ROS1 in biomarkers routine screening. Survival data and duration of response will be presented.

Background:
Non-small cell lung cancer (NSCLC) patients with ROS1 chromosomal rearrangement benefit from treatment with the ROS1 inhibitor crizotinib with remarkable response rates and durable disease control. Similar to ALK and EGFR mutant NSCLC treated with targeted kinase inhibitors, disease progression inevitably occurs due to acquired resistance either by mutation within the kinase domain of ROS1 or via bypass signaling. However, limited data exists on the spectrum of resistance mechanisms in ROS1+ NSCLC. Here report on a novel bypass mechanism for ROS1 resistance discovered in a ROS1+ tumor sample from patient with acquired resistance to crizotinib in which an activating mutation in the KIT receptor (p.D816G) desensitize ROS1 cells to crizotinib inhibition.

Methods:
Patients with ROS1+ NSCLC treated with crizotinib who developed acquired resistance underwent biopsy of a progressing tumor. Tumor samples were analyzed for potential resistance mechanisms. Assessment of mutations within the ROS1 kinase domain was accomplished by direct sequencing of exons 35 thru exon 42 of ROS1 from genomic DNA isolated from FFPE tissue. The SNaPshot® Multiplex System was used to profile additional tumor related genes for mutations. The ROS1 rearranged cell lines, HCC78 and CUTO-2, were transduced with lentivirus to generate ectopic expression of the KIT[D816G] cDNA. Cell proliferation was assessed by an MTS assay and cellular signaling was measured by western blot analysis.

Results:
Sequencing of the patient’s post crizotinib sample showed no mutation in the ROS1 kinase domain. Additional mutational profiling by SNaPshot® revealed the acquisition of a KIT[D816G] mutation in the post-crizotinib sample that was not present in the pre-crizotinib tumor sample. HCC78 and CUTO-2 ROS1+ cell lines expressing the KIT[D816G] mutation were refractory to crizotinib by both cell proliferation assays and analysis of downstream signaling pathways. Both ROS1 and KIT activity had to be inhibited in order to suppress downstream signaling and proliferation in these cells.

Conclusion:
Activation of KIT by a gain-of-function mutation is a novel mechanism of resistance to crizotinib in ROS1 rearranged NSCLC. This bypass-signaling pathway serves as a ROS1 independent mechanism of progression, similarly to previously identified EGFR or RAS signaling pathways, and can potentially be targeted by KIT inhibitors.

Background:
Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in less than 1% of NSCLCs. Cell-based assays have demonstrated that NTRK1 rearrangement leads to expression of an oncogenic TrkA fusion protein. While inhibition of TrkA in preclinical models reduces TrkA auto-phosphorylation and cell proliferation, the clinical activity of TrkA inhibitors in NSCLCs harboring an NTRK1 fusion is not known. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor of TrkA, TrkB, TrkC, ROS1, and ALK, with IC50 values for kinase inhibition ≤ 2 nM.

Methods:
We used an anchored multiplex polymerase chain reaction (AMP) assay to screen for NTRK1 rearrangements (Zheng et al., Nature Medicine 2014). Among over 663 NSCLC cases screened, we identified one positive case in which the 3’ end of SQSTM1 exon 6 was fused to the 5’ end of NTRK1 exon 10, leading to an SQSTM1-NTRK1 fusion transcript. We enrolled the patient onto the Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). The dose of entrectinib was 400 mg/m[2] (750 mg) once daily. We assessed safety of entrectinib and response to treatment using RECIST 1.1.

Results:
The patient is a 46 yo male with a 30 pack year smoking history who was first diagnosed with metastatic NSCLC in November 2013. Prior therapies included carboplatin/pemetrexed, pembrolizumab, docetaxel, and vinorelbine. At the time of study enrollment, the patient had an ECOG performance status of 2 and required supplemental oxygen at a rate of 3 liters per minute by nasal cannula. He reported significant pain and dyspnea due to widely metastatic disease, including a large left hilar mass narrowing the left upper lobe bronchus and obstructing the left lower lobe bronchus, extensive and palpable neck and chest lymphadenopathy, and a palpable expansile left chest wall mass. Staging head CT also revealed numerous (15 to 20) asymptomatic brain metastases measuring up to 1.7 cm that had not been previously treated. The patient was started on entrectinib and tolerated the study medication well, with one adverse event of grade 1 dysgeusia, which resolved after two weeks. Within three weeks of starting treatment, the patient reported resolution of dyspnea and pain, and improvement in energy and appetite. He no longer required supplemental oxygen and all sites of palpable disease had improved or resolved. At four weeks of treatment, restaging CT scans demonstrated a partial response by RECIST of -47%, with significant regression or resolution of lymphadenopathy, reduction in size of the chest wall mass, and marked reexpansion of the left lung. Restaging of the CNS by head CT demonstrated near complete resolution of previously visualized brain metastases.

Conclusion:
In a heavily pre-treated patient with NSCLC harboring an NTRK1 gene fusion, entrectinib therapy resulted in rapid clinical improvement and a radiologic partial response at 4 weeks with minimal toxicity. This preliminary report suggests that entrectinib may be an effective therapy for patients with NTRK1-rearranged NSCLC.

Abstract not provided

Background:
FGFR1 amplification is one of the most common potential driving oncogenes in squamous cell carcinoma (SCC), which accounts for 20% of non-small cell lung cancer (NSCLC) squamous cell carcinoma. This phase II study evaluated the efficacy and toxicity profile of dovitinib, an orally active FGFR (fibroblast growth factor receptor) inhibitor, in advanced SCC patients.

Methods:
Patients with histological confirmed advanced squamous cell NSCLC and previously treated with at least one cytotoxic chemotherapy were enrolled from April 2013 to December 2014. All patients had FGFR1 gene amplification more than 5 copies by fluorescent in situ hybridization (FISH). Each 7-day treatment cycle consisted of dovitinib 500mg orally administration on days 1 to 5 and 2 days off. Primary endpoint was overall response rate and secondary endpoints included PFS, OS and toxicity.

Results:
All 26 patients were male with the median age of 68 years (range, 52 – 80). Most patients were ever smokers (96%) and had good ECOG (0-1) performance status (85%). The median number of dovitinib treatment cycles administered was 2.5 (range, 1-12). The overall response rate (ORR) was 11.5% (95% CI, 0.8 – 23.8) and disease control rate (DCR) was 50% (95% CI, 30.8 – 69.2). There were three partial responses (PR) and ten stable diseases (SD). Duration of response in 3 patients who achieved PR was 4.5+, 5.1+ and 6.1months. After the median follow-up duration of 15.7 months (range, 5.8 – 25.6 ), the median overall survival (OS) was 5.0 months (95% Confidential Interval, 3.61 – 6.39) and progression-free survival (PFS) was 2.9 months (95% CI, 1.54 – 4.26). Grade 1/2 fatigue (69%) and anorexia (85%) were most commonly reported adverse events and 12 patients (46%) required dose reduction of dovitinib.

Conclusion:
Dovitinib treatment a showed modest efficacy in advanced squamous cell lung cancer patients with FGFR1 amplification. Further studies to evaluate other biomarkers correlated with the efficacy of dovitinib in SCC should be warranted.

Background:
In non-squamous non-small cell lung cancer (NSCLC), PI3-kinase (PI3K) pathway activation, including downregulation of phosphatase and tensin homolog (PTEN) expression, may promote cell survival and enhance chemotherapy resistance. Additionally, mutations in KRAS have been shown preclinically to confer resistance to PI3K inhibition. The pan-PI3K inhibitor pictilisib potentiates the activity of taxanes, platinum agents, and antivascular endothelial growth factor therapy in preclinical models of NSCLC. This phase II hypothesis-generating study (NCT01493843) evaluated the safety and efficacy of pictilisib in combination with carboplatin, paclitaxel, and bevacizumab in patients not treated for advanced or recurrent non-squamous NSCLC.

Methods:
Overall, 158 patients were randomized to receive carboplatin (area under the curve [AUC] = 6 mg/ml/min), paclitaxel (200 mg/m[2]), and bevacizumab (15 mg/kg) every 3 weeks (q3w) with 340 mg oral pictilisib (n=79) or placebo (n=79) daily in the first 2 weeks of each cycle for a total of 4 cycles. Bevacizumab q3w with daily pictilisib or placebo was continued until disease progression or unacceptable toxicity. Stratification factors included Eastern Cooperative Oncology Group performance status and smoking status. The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population and in patients with PTEN null/low expression (assessed by immunohistochemistry). Overall survival (OS), objective response rate (ORR), and safety were secondary endpoints. Pre-planned exploratory analyses included efficacy in the KRAS-wildtype subgroup. Tumor assessment was based on RECIST v1.1. Safety analyses were performed on patients who received at least one dose of study drug.

Results:
Median PFS in the ITT population was 6.9 months in the pictilisib arm and 5.9 months in the placebo arm (HR 0.82; 90% CI 0.59–1.13), while median OS was 13.6 months (pictilisib arm) versus 16.1 months (placebo arm) (HR 1.12; 90% CI 0.79–1.59). In patients with PTEN null/low expression, median PFS was 5.9 months (pictilisib arm) and 5.7 months (placebo arm) (HR 0.74; 90% CI 0.41–1.32). In the KRAS-wildtype subgroup, median PFS was 9.7 months (pictilisib arm) versus 5.7 months (placebo arm) (HR 0.70; 90% CI 0.45–1.09); median OS was 14.5 months in both arms. ORR in the ITT population was 37% (pictilisib arm) versus 29% (placebo arm). In the pictilisib arm, common grade ≥3 adverse events (AEs) included neutropenia (23%), rash (20%), thrombocytopenia (8%), febrile neutropenia (5%), and hyperglycemia (5%). AEs led to higher rates of discontinuation in the pictilisib arm (26% versus 16% in the placebo arm), particularly during the first 4 cycles. However, the proportion of AE-related deaths was higher in the placebo arm (9 [12%] versus 5 [6%] in the pictilisib arm).

Conclusion:
This phase II trial of first-line pictilisib plus chemotherapy and bevacizumab in patients with non-squamous NSCLC showed a modest trend for improved PFS, with additional toxicity and no OS benefit. The safety profile was consistent with other pictilisib trials. PTEN null/low expression was not a predictive biomarker, although its prognostic value cannot be excluded. A trend for improved PFS, but not OS, was observed in the KRAS-wildtype subgroup, especially during the maintenance phase of treatment.

Background:
In squamous non-small cell lung cancer (NSCLC), the PI3-kinase (PI3K) pathway may be activated via several mechanisms including PIK3CA amplification and downregulation of phosphatase and tensin homolog (PTEN) expression; activation of this pathway can promote cell survival and enhance chemotherapy resistance. Pictilisib, a pan-PI3K inhibitor, potentiates the activity of taxanes and platinum agents in preclinical NSCLC models. This phase II, hypothesis-generating study (NCT01493843) evaluated the safety and efficacy of pictilisib in combination with carboplatin and paclitaxel in patients with advanced or recurrent squamous NSCLC.

Methods:
Overall, 160 patients were randomized to receive carboplatin (target area under the curve [AUC] = 6 mg/ml/min) and paclitaxel (200 mg/m[2]) every 3 weeks with 340 mg oral pictilisib (n=81) or placebo (n=79) daily in the first 2 weeks of each cycle for a total of 4 cycles. Pictilisib or placebo was continued daily until disease progression or intolerable toxicity. Stratification factors included Eastern Cooperative Oncology Group performance status and smoking status. The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population and in patients with PIK3CA amplification (assessed by chromogenic in situ hybridization [CISH]). Overall survival (OS), objective response rate (ORR), safety, and PFS in the PTEN null/low subgroup were secondary endpoints. Tumor assessment was based on RECIST v1.1. Safety analyses were performed on patients who received at least one dose of study drug.

Results:
Median PFS in the ITT population was 5.6 months in the pictilisib arm and 5.5 months in the placebo arm (HR 0.82; 90% CI 0.60–1.12). Median OS was 11.7 months in the pictilisib arm and 12.2 months in the placebo arm (HR 1.10; 90% CI 0.77–1.57). PFS and OS analyses in patients with PIK3CA amplification will be presented. Median PFS for the PTEN null/low subgroup was 6.7 months in the pictilisib arm and 5.5 months in the placebo arm (HR 0.69; 90% CI 0.42–1.13). ORR in the ITT population was 28% in the pictilisib arm and 34% in the placebo arm. Common grade ≥3 adverse events (AEs) included neutropenia (18%), rash (8%), and thrombocytopenia (7%). AEs led to higher proportion of discontinuations (22% in the pictilisib arm vs. 15% in the placebo arm) and AE-related deaths in the pictilisib arm (12 [14%] vs. 2 [3%] in the placebo arm). Deaths were due to disease progression or AEs typically reported in lung cancer. No unexpected safety signals were identified for pictilisib.

Conclusion:
In this first phase II trial of a PI3K inhibitor in first-line squamous NSCLC, the combination of pictilisib with chemotherapy introduced additional toxicity with a minimal PFS improvement and no OS benefit in the ITT population. The safety profile was consistent with other pictilisib trials. PTEN null/low expression did not identify a subgroup with significantly improved efficacy, although the prognostic value of PTEN as a biomarker in squamous NSCLC cannot be excluded. Efficacy analysis in the PIK3CA amplification subgroup is ongoing and will be presented at the conference.

Background:
This abstract is under embargo until September 9, 2015 and will be distributed onsite on September 9 in a Late Breaking Abstract Supplement.

Methods:


Results:


Conclusion:

Abstract not provided

Background:
ALK rearrangements in non-small cell lung cancer (NSCLC) have been associated with younger age of onset, East Asian ethnicity, non- or light-smoking history, and adenocarcinoma histology. The objective of this study was to evaluate data from two retrospective multicenter chart review studies conducted in 2013 and 2014 to assess characteristics of ALK+ NSCLC patients and further understand the epidemiology of ALK rearrangements in NSCLC patients.

Methods:
This analysis included data from two chart review studies of patients diagnosed with locally-advanced or metastatic ALK+ NSCLC conducted among two separate panels of US oncologists. In the first study conducted in September and October 2013, 27 oncologists contributed data on 273 patients; in the second study conducted between July and November 2014, 49 oncologists contributed data on 153 patients. In both studies, collected information included the age at diagnosis of NSCLC, sex, ethnicity, smoking history at primary NSCLC diagnosis, and tumor histology. Data from these studies were analyzed to assess ALK+ NSCLC patient characteristics.

Results:
Patients from the 2014 cohort tended to be younger than patients from the 2013 cohort at diagnosis of locally-advanced or metastatic NSCLC (Table). In both cohorts, a little over half of the patients were male. Racial composition was diverse in both patient groups. Patients had varied smoking histories in both studies, with approximately one third of patients reported as never-smokers, one third as light smokers, and one third as moderate/heavy smokers. Tumor histology was heterogeneous in both cohorts. However, a particularly large proportion of patients in the 2014 cohort had squamous cell histology (14%).

Table. Characteristics of ALK+ NSCLC Patients from the 2013 and 2014 Studies

	2013 Study[1] N=273	2014 Study N=153
Age (years), median (IQR)	67 (58-72)	59 (52-67)
Male (%)	52%	57%
Race/Ethnicity (%)
Caucasian	59%	63%
Black/African American	18%	14%
Asian	13%	14%
Hispanic/Latino	8%	2%
American Indian/Alaska Native	1%	6%
Unknown	0%	1%
Smoking History[2] (%)
Never	33%	27%
Light	33%	24%
Moderate/heavy	33%	37%
Unknown[3]	1%	13%
Cancer Histology[2] (%)
Adenocarcinoma	81%	65%
Squamous cell carcinoma	3%	14%
Large cell carcinoma	5%	8%
Mixed	11%	9%
Unknown	0%	4%

Notes: IQR = inter-quartile range [1] Wakelee HA, Sasane M, Zhang J, et al. Description of ALK+ NSCLC patient characteristics and ALK testing patterns. J Clin Oncol 32:5s, 2014 (suppl; abstr 8062). [2] Reported at primary NSCLC diagnosis. [3] Includes patients with unreported smoking history as well as 16 former smokers in the 2014 study with unknown smoking histories.

Conclusion:
Assessment of patient characteristics in the two chart reviews suggests that ALK+ NSCLC patients may have diverse characteristics with varied racial composition, smoking histories, and tumor histology to an extent not previously detected. These results suggest that physicians may be testing NSCLC patients more frequently, yielding more diverse histology than expected among ALK+ tumors. Molecular testing could be informative for all newly diagnosed NSCLC patients, including patients with squamous cell histology.

Background:
Clinical trials have shown superior efficacy of ALK inhibitors compared with chemotherapies for patients diagnosed with ALK+ non-small cell lung cancer (NSCLC). In Korea, crizotinib was approved for ALK+ NSCLC in 2011 but is not yet reimbursed. The objective of this study was to describe real-world patient characteristics, ALK testing and treatment patterns, and survival among Korean patients diagnosed with locally-advanced or metastatic ALK+ NSCLC.

Methods:
A retrospective patient chart review was conducted in two major cancer centers in Korea. Participating physicians (N=4) reviewed patient charts and reported patient characteristics, ALK testing and treatment patterns, and survival of patients diagnosed with ALK+ locally-advanced or metastatic NSCLC. ALK inhibitor treatment duration and overall survival (OS) were estimated using Kaplan-Meier analyses.

Results:
In late 2014, 55 ALK+ NSCLC patients were identified for this study. The median follow-up time among these patients was 24.8 months. The median age at locally advanced or metastatic NSCLC diagnosis was 60 years (interquartile range: 52 - 67); 53% of patients were female, 51% were never-smokers, 2% were former smokers, 33% were current smokers, 15% had unknown smoking status, and 98% were diagnosed with adenocarcinoma. At primary diagnosis, 67% of patients had metastatic disease. ALK rearrangement was confirmed by fluorescent in situ hybridization (78%) or immunohistochemistry (22%). 27% of patients had their ALK rearrangement detected more than three months after their locally-advanced or metastatic diagnosis. The majority of patients received initial systemic chemotherapy; only 13% received an ALK inhibitor in the first-line, and 62% received an ALK inhibitor by the end of follow-up. Out of 30 patients who received crizotinib, 83% discontinued (median duration of 6.3 months) and 13% died while still on crizotinib. Of those who discontinued, 32% switched to chemotherapy, 16% switched to a different ALK inhibitor, and 52% received no further antineoplastic therapy. After discontinuing crizotinib, the median OS was 4.3 months.

Conclusion:
In this study of locally-advanced or metastatic ALK+ NSCLC patients in Korea, OS was poor following discontinuation of crizotinib with a median survival of 4.3 months. Additionally, many patients had delays in receiving ALK testing. Among patients who failed crizotinib treatment, over half received no further antineoplastic therapy. These findings suggest the need to provide timely access to ALK testing and effective treatments following crizotinib discontinuation for ALK+ NSCLC patients in Korea.

Background:
Crizotinib is an oral small-molecule tyrosine kinase inhibitor, which was approved in the United States (US) in August of 2011 for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). There are currently limited data on crizotinib treatment and related outcomes in ALK-positive advanced NSCLC patients with brain metastases at diagnosis in real world settings. The main objective of the current analyses was to assess and report the response rates in the ALK-positive advanced lung cancer patients with brain metastases treated with crizotinib in regular clinical practice.

Methods:
Physicians in the US (N=107) and Canada (N=40) were recruited from cancer centers or teaching hospitals (48%) or free standing oncology clinics (47%) to abstract data retrospectively from medical records of adult (≥18 years) patients diagnosed with ALK-positive advanced NSCLC and treated with crizotinib as first- or later-line therapy from 8/1/2011-3/31/2013 (for the US) or 4/12012-3/31/2013 (for Canada) in non-clinical trial settings. IRB approval was obtained. A secure web-based form was used by physicians to abstract data and all patient data were de-identified and anonymous. Descriptive analyses were conducted to summarize objective response rate (ORR) in the subgroup with brain metastases. One-year survival rates from initiation of crizotinib were descriptively analyzed for the subgroup with brain metastases using the Kaplan-Meier method.

Results:
Data were extracted from 212 patient records in US (N=147) and Canada (N=65), which included 33 ALK-positive advanced NSCLC patients with brain metastases present prior to crizotinib initiation. The mean (SD) patient age at diagnosis for these 33 patients was 57.4 (12.0) years and a majority were male (58%), Caucasian (76%), current or former smokers (67%), ECOG status 0 or 1 (55%), adenocarcinoma histology (85%) and initially diagnosed at the locally advanced or metastatic stage (70%). The majority (71%) of these patients had been treated with either whole brain radiotherapy (16 patients) or stereotactic radiosurgery (8 patients) prior to initiation of crizotinib treatment. Of these 33 patients, 21 received crizotinib as 1[st] line therapy for advanced ALK-positive NSCLC. Approximately 61% were alive at time of medical record data abstraction. The ORR was estimated to be 61% and 60% for these patients with brain metastases who received crizotinib as 1[st] and later line treatment, respectively. The Kaplan-Meier estimates of 1-year survival from crizotinib initiation were 81% and 77% in patients with brain metastases, who received crizotinib as 1[st] line and later line treatment, respectively.

Conclusion:
In ALK-positive advanced NSCLC patients with brain metastases, complete or partial response was reported in majority of patients during treatment with crizotinib in real world settings.

Background:
The ongoing multicenter, randomized, open-label phase III study PROFILE 1014 recently demonstrated superior efficacy of crizotinib compared with chemotherapy in patients with previously untreated advanced ALK-positive NSCLC (Solomon et al, N Engl J Med 2014). Intracranial efficacy of crizotinib vs. chemotherapy was compared prospectively in this trial.

Methods:
Patients with previously untreated advanced non-squamous ALK-positive NSCLC (N=343) were randomized 1:1 to receive crizotinib 250 mg orally BID (n=172) or intravenous chemotherapy (pemetrexed 500 mg/m[2 ]+ cisplatin 75 mg/m[2] or carboplatin at AUC 5–6; all q3w for ≤6 cycles; n=171). Patients with treated brain metastases that were stable for ≥2 weeks with no ongoing requirement for corticosteroids were eligible. Treatment was continued until PD. Continuation of, or crossover to, crizotinib after PD (per independent radiology review [IRR]) was allowed for patients randomized to crizotinib or chemotherapy, respectively. Brain scanning was performed every 6 weeks in patients with baseline brain metastases and every 12 weeks in those without baseline brain metastases. Protocol-specified efficacy endpoints included PFS (primary endpoint), ORR, OS, and 12- and 18-month OS, as well as intracranial TTP. Intracranial DCR at 12 and 24 weeks was also evaluated. Efficacy was evaluated in the ITT population and in two subgroups of patients: those with and without baseline brain metastases.

Results:
Of 343 patients in the ITT population, 79 had brain metastases at baseline identified by IRR (23%) and 263 did not (77%; data not reported for one patient). Baseline characteristics of patients randomized to receive crizotinib or chemotherapy were generally well balanced within these two patient subgroups. Among the patients with baseline brain metastases, a significantly higher proportion achieved intracranial disease control with crizotinib than with chemotherapy at 12 weeks (33/39 [85%] vs. 18/40 [45%], respectively; P=0.0003) and at 24 weeks (22/39 [56%] vs. 10/40 [25%]; P=0.006). There was a numerical improvement in prospectively measured intracranial TTP with crizotinib in the ITT population (HR 0.60, P=0.069), as well as in patients either with baseline brain metastases (HR 0.45, P=0.063) or without baseline brain metastases (HR 0.69, P=0.323). The frequency of progression in the brain was low in the ITT population (15%) and in patients with and without baseline brain metastases (27% and 11%, respectively). Overall PFS was significantly longer with crizotinib than with chemotherapy in both subgroups (brain metastases present: HR 0.40, P=0.0007, median 9.0 vs. 4.0 months; brain metastases absent: HR 0.51, P≤0.0001, median 11.1 vs. 7.2 months), as it was in the ITT population (HR 0.45, P<0.0001, median 10.9 vs. 7.0 months). Twenty-five patients in the crizotinib arm of the study experienced intracranial PD; 22 of these patients received crizotinib for ≥3 weeks beyond PD and 19 also received intracranial radiotherapy.

Conclusion:
In this prospective assessment of intracranial efficacy, crizotinib demonstrated significantly greater intracranial disease control and overall efficacy compared with chemotherapy in patients with baseline brain metastases. These findings provide further confirmation of crizotinib as the standard of care for patients with previously untreated advanced ALK-positive NSCLC, including those patients with brain metastases at baseline.

Abstract not provided

Background:
Tyrosine kinase inhibitors (TKIs) have been associated with the development of a rare but serious and potentially fatal lung injury syndrome referred to as drug-induced interstitial lung disease (ILD). This has been best characterized for the epidermal growth factor receptor (EGFR) TKIs, with a typical presentation of delayed but rapidly progressive dyspnea leading to respiratory failure and death in up to one third of cases. While case reports of crizotinib-associated ILD have been published, little is known regarding the incidence, clinical characteristics, and mortality of crizotinib-associated ILD. In an effort to better understand this adverse event (AE), we performed a systematic review of respiratory-related events in the four largest clinical trials with crizotinib.

Methods:
An independent three-person panel composed of a pulmonologist, radiologist, and oncologist, none of whom were associated with any of the clinical studies, was convened to analyze respiratory AEs of grade ≥3 and any-grade AEs reported by the investigator as pneumonitis, ILD, or radiation pneumonitis in four crizotinib studies (PROFILE 1001, 1005, 1007, and 1014). After review by each panel member individually followed by consensus review, the events were classified either as disease progression or true respiratory AEs. Respiratory AEs were then further sub-classified as due to: 1) de novo ILD, 2) exacerbation or recurrence of pre-existing ILD, 3) concurrent illness (recurrence or progression of pre-existing condition), or 4) other toxicity not thought to be related to ILD (e.g. bacterial pneumonia).

Results:
There were a total of 1,669 patients in the four studies, among whom 446 events in 368 patients met the criteria for further analysis. Of these 446 events, 77 were attributed to progressive disease, 310 to other toxicity not thought related to ILD, 20 to de-novo ILD, 9 to concurrent illness, and 3 to exacerbation of underlying ILD. 27 cases (25 patients) were felt to have insufficient data to draw firm conclusions. Overall, the incidence of crizotinib-associated ILD was 1.2% (20/1,644) across the four studies, with no difference in incidence seen between Asian and Caucasian populations. The mean onset of ILD was 82 days. The mortality rate for patients identified with crizotinib-associated ILD was 50% (10/20). There was a trend towards improved survival if crizotinib was stopped rather than continued on presentation (64% [9/14] vs. 17% [1/6], P=0.065). Early administration of systemic corticosteroids did not seem to affect survival.

Conclusion:
This report represents the largest systematic review of TKI-associated ILD that has been performed by an independent multidisciplinary review panel. Crizotinib-associated ILD occurred in approximately 1.2% of patients who were administered crizotinib and displayed a characteristic pattern of delayed but rapidly progressive dyspnea and hypoxemia with a mortality of 50% (10/20). This pattern is similar to that seen with the EGFR TKIs, but appears to have a more delayed onset and a higher mortality rate. In contrast to EGFR TKI-associated ILD, which has a markedly higher incidence in the Asian population, there appears to be no such predilection for crizotinib-induced ILD. Immediate cessation of crizotinib may improve survival.

Background:
Crizotinib (XALKORI [TM], Pfizer) , a tyrosine kinase inhibitor targeting ALK, ROS1 and MET, is used for the therapy of advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Cardiac toxicity is one of its adverse events which may interrupt the administration of crizotinib. Elevation of CK-MB has been reported but it remains to be determined whether the level of CK-MB can reflect cardiac toxicity of crizotinib therapy. We investigated the clinical manifestations and relevant frequency of heart-related side effects in 94 advanced ALK-rearranged NSCLC patients with treatment of crizotinib to share experiences of management of cardiac toxicity of crizotinib.

Methods:
A retrospective analysis was conducted to demonstrate the clinical manifestations as well as the corresponding frequency of cardiac toxicity in advanced ALK-rearranged NSCLC patients with treatment of crizotinib enrolled in our hospital in the past 4 years.

Results:
In the past 4 years, 95 advanced ALK-rearranged NSCLC patients were treated with crizotinib in our hospital, among which one patient dropped the treatment in 3 days due to grade 4 vomiting. In 94 eligible patients who continue the therapy more than one month, the heart-related side effects include QT interval prolongation (2/94), bradycardia (12/94), hypotension (3/94), aggravation of atrial fibrillation (1/94) and elevation of creatine kinase-MB(CK-MB) (59/94). Consequently, one of 2 patients with QT interval prolongation reduced dosage from 250 mg to 200mg twice daily for QT interval >500 ms on two electrocardiograms and then well tolerated. 12 patients with bradycardia presented asymptomatic and one patient with profound sinus bradycardia (heart rate [HR]≦45) continued crizotinib without dose reduction as she was asymptomatic and benefiting from continuous crizotinib treatment against the deadly disease. Patients with hypotension and aggravation of atrial fibrillation are tolerated and under close follow-up without dose reduction. Remarkably, we observed that majority of our patients (62.77%) experienced elevation of CK-MB and no correlation between age and CK-MB elevation (Pearson Correlation =-0.153，p=0.137).

Conclusion:
Cardiac toxicity is common during crizotinib treatment so that heart-related examinations, such as ECG as well as CK-MB, should be performed regularly especially for those with prior heart disease.

Background:
Crizotinib is an oral tyrosine kinase inhibitor that has been studied in patients with advanced ALK-positive non-small cell lung cancer and has demonstrated median therapy durations ranging from 23 weeks to 10.9 months. In the real-world setting, persistence and adherence to oral therapies may be suboptimal compared with physician-administered treatments. Little is known about crizotinib treatment experiences outside of clinical trials. The objective of this analysis was to evaluate persistence on and adherence to crizotinib using US pharmacy records.

Methods:
De-identified records from five closed-distribution US specialty pharmacies supplying crizotinib in the 50 states and US territories were analyzed. Patients with at least one record of a shipped crizotinib prescription between 8/30/2011 and 8/1/2014 were eligible. Persistence − the duration of time from initiation to discontinuation of therapy − was defined as the total number of days between the first and last prescription shipment dates plus the days' supply of the last prescription. Adherence − the extent to which a patient acts in accordance with the prescribed regimen − was evaluated using a medication possession ratio (MPR): the ratio of the total days' supply over the entire duration of therapy for patients with at least two crizotinib prescriptions. A grace period of 60 days between prescriptions was allowed. Sensitivity analyses of persistence and adherence were performed assuming grace periods between prescriptions of 30 and 90 days.

Results:
A total of 3845 crizotinib patients were identified and included in the analysis. Most were commercially insured (69%), <65 years of age (61%), and female (56%). The cohort was well balanced geographically. Most prescriptions (89%) were for doses of 250 mg BID. Average duration of therapy was 11.4 months (95% CI: 11.2−11.6), with a median of 7.5 months. 51% and 34% of patients remained on therapy at 6 and 12 months, respectively. 16% of patients remained on crizotinib >24 months (Figure 1). Figure 1 An average MPR of 95% was observed in the sub-cohort of 3072 patients with two or more prescriptions of crizotinib. Sensitivity analyses revealed that persistence (11.2−11.6 months) and adherence (93−96%) estimates were not impacted by the alternative grace-period definitions applied.



Conclusion:
In the real-world setting, the duration of crizotinib therapy was similar to that reported in clinical trials. Adherence to crizotinib was high and may be indicative of its acceptable tolerability. Further research is warranted to evaluate experiences associated with crizotinib using other real-world data sources.

Background:
Crizotinib, a standard care for advanced ALK-positive NSCLC, is a substrate for ABCB1-encoded P-glycoprotein, and is primarily metabolized by CYP3A4/5. The most common adverse events (AEs) are visual disorder, gastrointestinal disorders, and elevated transaminase levels. Serious AEs such as grade (Gr) ≥ 3 elevated transaminase levels and interstitial lung disease (ILD) occasionally develop.

Methods:
ALK-positive NSCLC patients were enrolled in cohort A (enrollment before starting crizotinib therapy) or cohort B (enrollment during crizotinib therapy). Trough concentrations of crizotinib at steady state were measured using LC/MS/MS and ABCB1 polymorphisms were analyzed. We evaluated clinically significant AEs, defined as Gr 4 hematological toxicity, Gr ≥ 3 non-hematological toxicity, or any ILD. AEs during 8 weeks were also evaluated prospectively on the patients enrolled in cohort A.

Results:
A total of 78 patients at 17 institutions were enrolled. In cohort A (n = 47), AEs which occurred in more than 40% of patients during 8 weeks were ALT increased (75.0%), visual disorder (47.2%), anorexia (45.5%), nausea (45.5%), and AST increased (43.2%). In both cohorts (n = 75), 26 clinically significant AEs (n = 25) were observed: Gr ≥ 3 elevated transaminase level (14.7%), ILD (4.0%), Gr 4 neutropenia (4.0%), Gr 3 thromboembolic event (4.0%), Gr 3 esophagitis (2.6%), and Gr 3 QTc prolongation (2.6%). There was one treatment-related death (1.3%) due to ILD. Clinically significant AEs tended to occur more frequently in females than males, albeit without significance (38.4% vs. 19.2%, respectively; p = 0.09). Blood samples for trough concentrations of crizotinib at steady state were collected from 63 patients. The geometric mean of trough concentrations were 396 (95% CI, 325-483) ng/ml in male and 395 (95% CI, 329-474) ng/ml in female, respectively (p=0.569, Mann-Whitney U test). No clinical factors including gender, weight, body surface area, and age which influenced trough concentrations or AEs of crizotinib were identified. Moreover, the trough concentration of crizotinib was not significantly different between patient with clinically significant and without (429 [95% CI, 361-509] ng/ml vs. 378 [95% CI, 313-456] ng/ml, respectively [p=0.365]).

Conclusion:
In this multicenter study, we observed crizotinib AEs as previously reported. Clinically significant AEs tended to occur more frequently in females than males, albeit without significance. Furthermore, we will present the association of clinically significant AEs and trough concentration with ABCB1 polymorphism.

Abstract not provided

Background:
The screening algorithm for detection of ALK-rearranged NSCLC is still under investigation. The Break-Apart ALK FISH is the standard diagnostic test for the treatment with crizotinib. However, immunohistochemistry (IHC) with different antibodies shows excellent results when compared to ALK FISH. The efficacy of crizotinib is studied in relation to ALK FISH. We compared IHC outcome and the number of ALK breaks estimated by FISH with clinical outcome and retested at disease progression on crizotinib treatment

Methods:
Patients treated with crizotinib who had biopsies with sufficient tumor tissue were selected. Tumor response was assessed by CT using RECIST v1.1. Fluorescence in situ hybridization (FISH) was performed with Vysis LSI ALK Break Apart FISH Probe KIT (Abbott Molecular Inc., Des Plaines, IL) and immunohistochemistry with Ventana (Ventana Medical Systems Inc, Tucson, AZ) ALK IHC Kit using D5F3 antibody. The same tests were performed on re-biopsy material after progression on crizotinib.

Results:
Twenty-nine patients with ALK positive advanced NSCLC were treated with crizotinib. Median (range) age was 54 yrs (21-75); 26 had an adenocarcinoma, 3 had large-cell carcinoma. We confirmed the presence of EML4-ALK fusions in all samples either by FISH or IHC. Median percentage of ALK breaks was 47% (2-76). Tumor responses occurred in 9 pts having a median of 51 (6-76) breaks per tumor sample. The 20 non-responders had a median of 27 (15-64) breaks per tumor sample with 64 being an outlyer. In IHC positive pts 9/11 had a response to crizotinib treatment. In those who were IHC negative no pts (0/14) had a response (12 PD; 2 SD). Median PFS for positive IHC is 7.9 mo (95% CI., 5.5 – 10.3) and for negative IHC 1.6 mo (1.3 – 1.8), n=17, p<0.0001. Overall survival is 6.5 mo (95% CI., 0 – 17.8) and 18.3 mo (95% CI., 11.1 – 25.6) respectively, n=29, p=0.05. In 8 pts with progressive disease re-biopsies were performed. Only in one pt FISH ALK became negative. In the other pts IHC and FISH remained both positive. In pts who progressed on crizotinib, 4 pts had extra red in the FISH, which may be treatment related.

Conclusion:
All IHC positive advanced NSCLC patients responded to crizotinib. Extra red in the FISH test may cause progression to treatment with crizotinib.

Background:
PROFILE 1014 compared the efficacy and safety of the ALK inhibitor crizotinib with platinum based chemotherapy in previously untreated advanced ALK-positive advanced NSCLC (Pfizer; NCT01154140). The primary endpoint was progression-free survival. The main objective of this post-hoc analysis was to compare patient-reported symptom and global quality of life (QOL) between crizotinib and chemotherapy in the subgroup of patients of Asian ethnicity in the ongoing study PROFILE 1014.

Methods:
Patients in the ongoing PROFILE 1014 study were randomized to crizotinib (250 mg PO bid; n= 172) or chemotherapy (pemetrexed 500 mg/m[2] + either cisplatin 75 mg/m[2] or carboplatin AUC 5–6; all IV q3w for ≤6 cycles; n= 171). Patient-reported outcomes were assessed at baseline, day 7 and day 15 of cycle 1, day 1 of subsequent 3-week cycles and end of treatment using the validated cancer specific questionnaire EORTC QLQ-C30 and its lung cancer module QLQ-LC13. Validated translations of the questionnaires in Asian languages (Japanese, Chinese, Korean etc) were made available. Higher scores (range 0−100) indicated higher symptom severity or better functioning/QOL. A positive change from baseline score indicates improvement for global QOL/functioning and deterioration in symptoms. Repeated measures mixed-effects analyses were performed to compare change from baseline scores between the treatment arms, with no adjustments made for multiple comparisons.

Results:
Of 343 patients randomized, 46% were of Asian ethnicity (crizotinib, n=77; chemotherapy, n=80). Completion rates at baseline were ≥95% in each group and scores were balanced. A statistically significantly greater overall improvement from baseline was observed with crizotinib compared with chemotherapy for global QOL (5.6 vs -7.7; p<0.001), emotional functioning (9.5 vs 2.7;p<0.05), physical functioning (5.0 vs - 2.7 p<0.001) and role functioning (3.7 vs. -7.2;p<0.001). A statistically significantly greater overall improvement was observed with crizotinib compared with chemotherapy for cough (-17.3 vs. -11.2; p<0.05), dyspnea (-9.5 vs.-1.1; p<0.001), pain in arm or shoulder (-11.4 vs.-2.2; p<0.001), pain in chest (-7.3 vs.3.3; p<0.001), pain in other parts (-11.2 vs. -0.4;p<0.001), fatigue (-9.9 vs. 3.9; p<0.001), insomnia (-10.3vs. -2.0; p<0.05), pain (-12.2 vs.-1.2; p<0.001) and appetite loss (-5.3 vs. 5.7; p<0.001). A statistically significantly greater overall deterioration was observed in the crizotinib arm for diarrhea (12.6 vs. 2.4; p<0.001) compared with chemotherapy. No statistically significant differences were observed for social functioning, sore mouth, dysphagia, nausea & vomiting, constipation and alopecia between crizotinib and chemotherapy.

Conclusion:
Consistent with previously reported results in the overall study population, treatment with crizotinib showed statistically significantly greater overall improvement in patient-reported lung cancer symptoms and global QOL compared with chemotherapy in the subgroup of patients of Asian ethnicity with previously untreated advanced ALK-positive NSCLC.

Background:
In the pivotal ASCEND-1 study, ceritinib, an anaplastic lymphoma kinase inhibitor (ALKi), showed clinical activity in patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC), including in patients with brain metastases (BrM). Here, patient-reported outcomes (PROs) from the recently reported ASCEND-2 study (NCT01685060) are described for chemotherapy- and ALKi-pretreated patients with ALK+ NSCLC with and without baseline BrM

Methods:
In ASCEND-2, adult patients with ALK+ NSCLC previously treated with chemotherapy and an ALKi (crizotinib) received oral ceritinib 750 mg daily. PROs were assessed at baseline and Day 1 of treatment cycles 2, 3, and every two cycles thereafter (1 cycle=28 days), using the Lung Cancer Symptom Scale (LCSS) and EORTC quality of life and lung cancer surveys (QLQ-C30 and QLQ-LC13, respectively). Data were analyzed by presence/absence of baseline BrM. Data beyond cycle 9 are not reported due to small sample sizes.

Results:
All 140 patients enrolled (median age [range] 51 [29–80] years; 50.0% male), had received ≥2 antineoplastic regimens and 100 (71.4%) had BrM at baseline. At data cutoff (13 August 2014), median follow-up was 11.3 months. PRO questionnaire compliance was at least 91.2% up to cycle 9. In the overall patient population, investigator-assessed disease control rate (DCR) was 77.1% and median duration of response (DOR) 9.7 months. Investigator-assessed whole-body DCR [95% confidence interval (CI)] in patients with and without baseline BrM was 74.0% [64.3, 82.3] and 85.0% [70.2, 94.3], respectively, while DOR [95% CI] was 9.2 [5.5, 11.1] and 10.3 [7.4, 16.6] months, respectively. Analysis of PROs data demonstrated that treatment with ceritinib improved lung cancer symptoms in patients with and without baseline BrM (Figure). QLQ-LC13 outcomes were broadly consistent with those of LCSS. In general, mean global quality of life (QLQ-C30) was maintained on treatment for both patient subgroups, with mean change from baseline in QLQ-C30 global health status ranging from -3.06 to +7.25 in patients without baseline BrM and -2.83 to +3.55 in those with baseline BrM. Figure 1



Conclusion:
In patients with ALKi-pretreated ALK+ NSCLC who received prior chemotherapy and ceritinib, clinical efficacy was demonstrated and cancer symptoms were mostly improved, with health-related quality of life generally maintained regardless of presence or absence of baseline BrM.

Background:
In the pivotal ASCEND-1 study, ceritinib, an anaplastic lymphoma kinase inhibitor (ALKi), demonstrated sustained clinical activity in ALKi-naive patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC), including in patients with brain metastases (BrM). ASCEND-3 (NCT01685138) evaluated patient-reported outcomes (PROs) as well as clinical outcomes with ceritinib, in ALKi-naive ALK+ NSCLC patients with and without baseline BrM.

Methods:
Adult patients with ALK+ NSCLC previously treated with up to 3 lines of cytotoxic therapy received oral ceritinib 750 mg daily. PROs were assessed using Lung Cancer Symptom Scale (LCSS) and EORTC (QLQ-C30, QLQ-LC13) quality of life and lung cancer surveys at baseline and Day 1 of treatment cycles 2, 3, and every two cycles thereafter (1 cycle=28 days). Data were analyzed by presence/absence of baseline BrM. Data beyond cycle 9 are not reported due to small sample sizes.

Results:
Of 124 enrolled patients (median age [range] 56 [27–82] years; 40.3% male), 50 (40.3%) had BrM at baseline. At data cutoff (27 June 2014), median follow-up was 8.3 months. Up to cycle 9, PRO questionnaire compliance was at least 97.0%. In the overall patient population, investigator-assessed disease control rate (DCR) was 89.5% and median duration of response (DOR) 9.3 months. Investigator-assessed whole-body DCR [95% confidence interval (CI)] in patients with and without baseline BrM was 86.0% [73.3, 94.2] and 91.9% [83.2, 97.0], respectively, while DOR [95% CI] was 9.1 [7.5, Not Estimable] and 10.8 [9.3, 10.8] months, respectively. Mean change from baseline in patients’ total LCSS score ranged from -3.4 to -11.4 while receiving ceritinib, with 82.1% of patients experiencing symptom improvement; symptoms improved in patients with and without baseline BrM (Figure). QLQ-LC13 outcomes were broadly consistent with those of LCSS in the full patient population and in the subgroups of patients with and without baseline BrM. In general, mean global quality of life (QLQ-C30) was maintained on treatment for all patients. Patients reported diarrhea and nausea and vomiting symptoms were worse than baseline, however, nausea and vomiting symptoms did reduce over time. Figure 1



Conclusion:
In ALKi-naive patients with ALK+ NSCLC, treatment with ceritinib demonstrated clinical efficacy and improved cancer symptoms, with health-related quality of life generally maintained regardless of baseline BrM status. Improvements were greatest for the lung-related symptoms, cough and pain.

Abstract not provided

Background:
Sentinel node (SN) is defined as the first node draining a tumor, and should be the first site affected in lymphatic dissemination. Recently, with the increased incidence of small sized non-small cell lung cancer (NSCLC), segmentectomy is again under evaluation for clinical T1a N0 NSCLC patients. In the ongoing trial regarding segmentectomy (JCOG0802), the eligibility criteria for segmentectomy include a prerequisite of no lymph node metastasis by intraoperative findings because node-positive cases have a chance to be locoregionaly controlled and to be correctly staged by converting to lobectomy. Therefore, intraoperative sampling and frozen sectioning of true SNs is important in ensuring the radicality of segmentectomy. The objective of this study was to assess the safety and the feasibility of computed tomography (CT) lymphography by transbronchial injection of a water-soluble extracellular CT contrast agent which was developed as a new method for identifying SNs in patient with NSCLC.

Methods:
Between April, 2010 and January, 2015, clinical stage I NSCLC patients who were candidates for lobectomy or segmentectomy were enrolled in this study. An ultrathin bronchoscope was inserted to the target bronchus under the guidance of virtual bronchoscopic navigation images. CT images of the chest were obtained 30 seconds after 2 or 3ml of iopamidol was injected through a microcatheter. SNs were identified when the maximum CT attenuation value of the lymph nodes in postcontrast CT images increased by 30 Hounsfield units or more compared to precontrast images. Patients underwent video-assisted thoracic surgery lobectomy with standard lymph node dissection. SNs were harvested according to findings of CTLG and to intraoperative findings of near-infrared fluorescence imaging with indocyanine green. All lymph nodes, including SNs, were histopathologically examined by standard hematoxylin and eosin staining.

Results:
The ultrathin bronchoscope could access targeted bronchus, and iopamidol was delivered into the peritumoral area in all 41 patients without any complications. SNs were identified in 38 of 41 patients (92.7%), and the average number of SNs was 1.4 (range: 1-4). Lymph node metastases were found in 6 cases, including one false-negative case. Enlargement of lymphatic vessel was seen in 3 out of 6 (50%) cases with lymph node metastases, whereas it was seen in 6 out of 35 cases (17%) without lymph node metastases.

Conclusion:
CT lymphography by transbronchial injection of iopamidol was a safe and feasible method to identify SNs in clinical stage I NSCLC patients. Lymphatic remodeling including peritumoral lymphangiogenesis and enlargement of lymphatic vessel has been reported to one of the crucial step of lymph node metastasis of cancer. Enlargement of lymphatic vessel seen in CT lymphography may be a risk factor for lymph node metastasis of NSCLC.

Background:
Lung cancer has been the leading cause of cancer related mortality for the past decades worldwide and in China. Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases. For patients with early stage NSCLC, surgical resection is the mainstay of the treatment. This study aimed to better understand characteristics of NSCLC patients who underwent curative-intent lung surgical resections in China.

Methods:
Data were obtained from the NSCLC surgical outcome registry, which included 3,464 NSCLC patients who underwent curative-intent surgical resections from 13 tertiary hospitals in 11 provinces in 2013 and 2014. The registry documented detailed information on demographics as well as perioperative parameters.

Results:
The median age at the time of surgery was 60 (range 14 to 92) years, and 64.0% of the patients were male. Approximately 49.1% had a smoking history and 12.6% had a family history of cancer. About 45.7% patients had at least one comorbidity. The most prevalent comorbidities were cardiovascular disease, metabolic disease, respiratory disease, and other tumor, which affected 45.2%, 15.5%, 13.3% and 9.7% of the patients, respectively. The pulmonary function test showed a mean FEV1 of 2.33 (SD=0.63, range 0.32 to 4.81) L and FEV1/FVC of 79.3% (SD=12.6%, range 0.5% to 100.0%). The types of resection were lobectomies (lobectomies, bi-lobectomies and sleeve lobectomies) 79.3%, sublobar resections (segmentectomies and wedge resection) 8.5%, pneumonectomies 7.0%, and others 4.3%. 44.5% resections were performed by video-assisted thoracoscopic surgery (VATS). Adenocarcinoma and squamous cell carcinoma were the most common types of NSCLC, accounting for 60.2% and 31.4% of the patients, respectively. The most common tumor locations were right upper lobe (26.9%), left upper lobe (22.8%), right lower lobe (19.4%), left lower lobe (16.5%), and right middle lobe (6.5%). Pathologic staging showed 48.5% patients had stage I tumor; stage II, III, and IV accounted for 23.0%, 25.3% and 3.3%.

Conclusion:
The NSCLC patients who underwent curative-intent lung resection surgeries in China were relatively young and had good lung function. Adenocarcinoma and squamous cell carcinoma were the most common types. Nearly half of the procedures were performed by VATS and almost one out of two patients had pathologic stage I disease.

Background:
Video-assisted thoracic surgery (VATS) plays an important role in thoracic surgery especially for early stage lung cancer because it is less invasive. However, the existence of severe pleural adhesions may make VATS difficult and complicated. So, preoperative detection of pleural adhesions can be very useful for the assessment of surgical approach. The aim of this study was to assess the accuracy of inspiration and expiration computed tomography (respiratory dynamic CT: RD-CT) in evaluation of pleural adhesions prior to thoracic surgery. Video-assisted thoracic surgery (VATS) plays an important role in thoracic surgery especially for early stage lung cancer because it is less invasive. However, the existence of severe pleural adhesions may make VATS difficult and complicated. So, preoperative detection of pleural adhesions can be very useful for the assessment of surgical approach. The aim of this study was to assess the accuracy of inspiration and expiration computed tomography (respiratory dynamic CT: RD-CT) in evaluation of pleural adhesions prior to thoracic surgery.

Methods:
From January to December 2014, RD-CT was performed on 107 patients undergoing thoracotomies (both VATS and open surgery, except for pneumothorax). We assessed synchronous motion during respiration on RD-CT using a three-dimensional CT image software, as Sliding Score. Regarding intraoperative findings, we categorized the severity of pleural adhesions into 4 groups as Adhesion Grade. Then, comparing Sliding Score and Adhesion Grade, we assessed the utility of preoperative evaluation. In addition, to confirm these patients could expire enough in expiration phase, we assumed lung volume in expiration phase/ inspiration phase as CT- Respiratory Ratio in each case.

Results:
Operations were performed mainly for lung cancer (78 cases; 72.9%), others are metastatic lung tumor, mediastinal tumor, lung abcess and so on. A negative correlation between Sliding Score and Adhesion Grade was revealed. Sliding Score in adhesion positive patients was significantly higher than that in adhesion negative patients (P < 0.0001). The sensitivity of RD-CT was 63.6%, specificity was 74.1%, and accuracy was 72%. Among 62 patients with a CT-Respiration Ratio of less than 0.65, the sensitivity of RD-CT was 77.8%, specificity was 86.8%, and accuracy was 85.5%. Regarding severe adhesions, RD-CT demonstrated a sensitivity of 100% in all 107 patients. No significant correlation was revealed between CT- Respiratory Ratio and respiratory function or Adhesion Grade.

Conclusion:
RD-CT may be useful for detecting the presence of pleural adhesions, especially to rule out the severest adhesions. It can be adopted as one of the criteria for deciding the surgical approach, VATS or open surgery. And it may enable an operation to be performed more safely and systematically.

Background:
In our model of Combined Clinical Staging (CCS) for lung cancer, patients with a Computerized Tomography (CT) scan of the chest that does not show distant metastases will then routinely undergo whole body Positron Emission Tomography (PET/CT) and Magnetic Resonance Imaging (MRI) of the brain prior to any therapeutic decision. We aim to determine the accuracy of CCS and the value of brain MRI in this population.

Methods:
A prospective database was queried for all patients who underwent resection of lung cancer from 01/2012 to 06/2014. Demographics, wait times, clinical and pathological stage (7[th] edition AJCC/UICC), and costs of staging were collected. Krippendorff’s alpha was used to determine correlation between clinical and pathological stage.

Results:
Of 315 patients with primary lung cancer, 55.6% were female and the median age was 70 (27-87, Table 1). The mean time from initial CT scan to surgical treatment was 9.12 +/- 6.0 weeks. Krippendorff’s alpha between CCS and pathological stage was 0.193 (0.125 to 0.260, Table 2). When correlation was analyzed without consideration for sub-stages A and B, 49.8% (157/315) of patients were staged accurately, 39.7% (125/315) were over-staged, and 10.5% (33/315) were under-staged. Only 4.7% (15/315) of patients underwent surgery without appropriate neo-adjuvant systemic treatment. Preoperative brain MRI detected asymptomatic metastases in 4/315 patients (1.3%). At a median postoperative follow-up of 16 months (1-40), 7 additional patients developed symptomatic brain metastases, all of which had normal brain MRI preoperatively. The total cost of CCS was $416,924 over the study period, with $131,824 (31.6%) going towards brain MRI.

Table 1: Baseline descriptive data, N=315

Age Mean (SD)	69.80 (9.62) (Min: 27.34, Max: 86.61)
Gender
Female (%)	175 (55.6%)
Male (%)	140 (44.4%)
Weeks First Visit to Consent Mean (SD)	5.49 (8.15) (Min: 0, Max: 63)
Weeks Consent to Surgery Mean (SD)	2.24 (2.07) (Min: 0, Max: 11)
Weeks Initial CT to Surgery Mean (SD)	9.12 (6.01) (Min: 0, Max: 53)
Weeks First Visit to Surgery Mean (SD)	8.00 (8.25) (Min: 0, Max: 64)
Brain Metastases at Baseline (%)	4 (1.3%)
Brain Metastases at Follow Up (%)	11 (3.5%)

Table 2: Frequency and agreement of CCS and pathological stage

Stage (N=315)	Clinical Stage N (%)	Pathological Stage N (%)	Same Staging by Both (True Positives)
0	1 (0.3%)	-	-
Stage IA	89 (28.3%)	103 (32.7%)	55
Stage IB	39 (12.4%)	82 (26.0)	19
Stage IIA	42 (13.3%)	47 (14.9%)	7
Stage IIB	32 (10.2%)	42 (13.3%)	12
Stage IIIA	78 (24.8%)	39 (12.4%)	16
Stage IIIB	21 (6.7%)	0 (0.0%)	0
Stage IV	13 (4.1%)	2 (0.6%)	2
Krippendorff's Alpha for level of agreement = 0.193 (0.125 to .260)

Conclusion:
CCS is effective for patients with resectable lung cancer, with less than 5% of patients being under-staged in a way that denied them appropriate systemic treatment before surgery. Brain MRI is a low yield and high cost intervention in this population, and its routine use should be questioned.

Background:
The noninvasive dynamic characterization of hypoxia using molecular imaging approaches is supportive for evaluation of malignant tumor. In this study, we evaluated the clinicopathological impact of newly developed tumor hypoxia PET tests for localized non-small cell lung cancer (NSCLC).

Methods:
Forty-nine patients with localized NSCLC were enrolled[F1] [木下智成2] . They underwent chest hypoxia PET tests, namely [18]F-fluoroazomycin arabinoside (FAZA) and/or [62]Cu-diacetyl-bis (N4)-methylsemithiocarbazone (ATSM) PET in addition to routine whole-body [18]F-fluorodeoxyglucose (FDG) PET before treatment. Uptake of hypoxic tracers was quantified by calculating maximum standard uptake values (SUVmax) and tumor muscle ratios (TMR).

Results:
The uptake of [18]F-FAZA were in positive proportion to that of [62]Cu-ATSM (P < 0.05). Neutrophil lymphocyte ratio and tumor size were significantly correlated with uptake both in [18]F-FAZA (P < 0.01) and [62]Cu-ATSM (P < 0.05 in [18]F-FAZA and [62]Cu-ATSM). Pathologically, the case with vascular or pleural invasion, which indicate tumor malignancy, had higher uptake of [18]F-FAZA (P < 0.05). Those accumulations increased according to advanced TNM staging (P < 0.05). The patient with higher uptake of these tracers significantly had a poorer overall survival (P < 0.01 in [18]F-FAZA and P < 0.05 in [62]Cu-ATSM), and progression-free survival (P < 0.01 in [18]F-FAZA and P < 0.05 in [62]Cu-ATSM).

Conclusion:
[18]F-FAZA and [62]Cu-ATSM can provide useful information on tumor malignancy and prognosis, and might contribute toward guiding individualization of treatment of localized NSCLC. Figure 1Figure 2

Background:
New technologies in radiotherapy of lung tumours aim to reduce toxicity and increase tumour control by increasing the dose delivered, and reducing the size of radiotherapy margins. Kilovoltage intrafraction monitoring (KIM) is a novel image guidance technology, which permits visualisation of fiducials implanted into the tumour whilst the radiotherapy beam is on. KIM has been used in both prostate[1] and liver tumours[2], and has been shown to increase the accuracy of radiotherapy delivery. In this Phase I study we aim to establish whether it is feasible to use KIM to monitor the motion of lung tumours during radiotherapy delivery. 1. Ng J et al. IJROBP 2012:84(5):e656 2.Poulsen P et al. Radiotherapy and Oncology 2014:111(3):424

Methods:
Patients receiving curative radiotherapy for lung cancer will have between 3-5 fiducials inserted into their tumour during endobronchial ultrasound (EBUS). Radiotherapy will be planned and delivered as per standard departmental protocols for lung cancer patients. 4D-cone beam CT (CBCT) will be performed , in conjunction with acquisition of KIM images and respiratory motion signal acquisition on the 1[st], 6[th], 11[th], 16[th], 21[st], 26[th], and 30[th] fractions before treatment to assess the accuracy of patient and tumour position.

Results:
Initial studies in a respiratory motion phantom have indicated that 0.4mm diameter Gold Anchor fiducials are visible during radiotherapy treatment. Ethical approval has been obtained with patient recruitment to the study to commence shortly. The primary endpoint of this study is the successful visualisation by the KIM technique of fiducials inserted into the tumour. Each patient will have a minimum of 3 fiducials (markers) inserted. As the implanted fiducials may be migrated or lost, the definition of technical success will vary according to the number of fiducials present. In the case of 1 to 3 markers being present, segmentation of at least 1 marker will be required for the image acquisition to be deemed successful. In the case of 4 or more fiducials being present, segmentation by the KIM technique of at least 2 markers for each image will be required for the image acquisition to be deemed successful. Secondary endpoints include assessment of the stability of implanted markers, and the rate of marker migration, quantitative assessment of tumour motion, assessing the impact of tumour motion on dosimetry and an assessment of toxicity associated with marker insertion.

Conclusion:
Lung tumours move during radiotherapy treatment, both between radiotherapy fractions and whilst the radiotherapy dose is being delivered[3]. Establishing the feasibility of KIM will enable the visualization of tumour motion whilst the radiotherapy treatment is being delivered. This is currently impossible on a standard linac, limiting the ability of the clinician to implement changes in margin size, which could potentially reduce the severity of side-effects for patients. Assessing intra-fraction motion of lung tumours is a key step in this process – by identifying the uncertainty in treatment, we will in the future be able to implement gating and tracking of tumours, thus resulting in safer and more effective treatment. 3. Sonke J. et al. IJROBP 2008:70(2):590

Background:
We recently reported an association between progression-free survival and metformin exposure in patients with early stage non-small cell lung cancer (NSCLC). Local recurrence in stage I disease is estimated to be as high as 50% in US populations. Therefore, a method to identify NSCLC patients who are most likely to benefit from metformin treatment has potential clinical relevance.

Methods:
Three previously published, publically available gene expression array data sets documenting the effects of metformin treatment on transcriptional activity in human cell lines were used for the initial stages of the present study. These data sets were evaluated individually for enrichment of differentially expressed genes with a gene set analysis related to biological processes also performed. Differentially expressed genes common to all three studies were then used to form a metformin meta-gene. This combined meta-gene was evaluated topologically using a protein-protein interaction database to determine if any gene products had previously observed direct interactions. The metformin meta-gene network was then examined in expression array data sets from stage I NSCLC patients (n=293) assembled from multiple published studies.

Results:
We identified several biological themes resulting from metformin treatment, including: immune cell differentiation, response to hypoxia, steroid receptor signaling, alternate splicing, and changes in cellular metabolism. Intersecting the differentially expressed genes from each data set, we identified 105 genes consistently up-regulated and 30 genes consistently down-regulated by metformin treatment, forming a tissue-independent meta-gene for metformin effects. Two networks of interacting genes were identified in this analysis; the first network consisting of 27 genes (22 up-regulated and 5 down-regulated) and the second consisting of three up-regulated genes.This meta-gene was then examined in two independent cohorts of stage I adenocarcinoma. In the first cohort (n=125), patients clustered into two groups when k-means analysis was performed with respect to the 30 genes in the metformin meta-gene network. These patients had a significantly (p=0.014) different incidence of recurrence between the two clusters. This result was independently validated in the second data set (n=168) where patients clustered into two groups and also demonstrated significant stratification of recurrence (HR=1.21; p=0.001).

Conclusion:
We have identified a meta-gene of interacting proteins associated with both metformin therapy and recurrence-free survival in early stage lung cancer patients. This suggests a potential method for identifying NSCLC patients most likely to benefit from metformin therapy, and furthermore, identifies mechanistic avenues by which metformin treatment may benefit early stage lung cancer patients.

Background:
Serum based biomarkers are routinely used for prognosis and monitoring of some solid tumors (e.g. colorectal, pancreatic, and ovarian carcinomas) but have not yet been widely adopted in NSCLC management. We prospectively evaluated the prognostic role of serum biomarkers in the management of early stage NSCLC treated at a single specialized center.

Methods:
Prospective collection of blood samples from patients (pts) with resectable NSCLC was done before surgery and thereafter during routine follow up visits. A panel of serum biomarkers was measured, including CYFRA 21-1 (Cytokeratin fragment 19) and CEA (carcinoembryonic antigen). Several risk models were established and prediction accuracy was assessed by C-Index (generalized AUC), Hazard Ratio (HR) at median split and Net Reclassification Index (NRI).

Results:
275 pts were enrolled (n= 180 men). Histology was adenocarcinoma (AC) in 133 pts (48.4%), squamous cell carcinoma in 103 pts (37.5%), and other in 39 (14.1%). Stages were based on IASLC 6[th] edition and included IA (n= 39), IB (n= 120), IIA (n= 7), IIB (n= 66), and IIIA (n= 43). 92 pts (33.5%) recurred after a median of 11.9 months follow-up. Occurrence of first relapse showed two main peaks, at 6-12 months and 21-27 months, respectively, indicating a high-risk group for early relapse. In multivariate analyses, clinical prognostic factors included: TNM stage, age, gender, histology, and smoking history. Addition of the baseline CYFRA 21-1 and CEA biomarkers significantly increased the number of pts allocated to the correct prognostic group in the model by 13.2% compared to clinical variables only (HR for first relapse from 2.14 to 3.02; NRI 0.132).

Conclusion:
In this largest cohort of NSCLC pts with prospective serum biomarker sample collection to date, time to first relapse in localized NSCLC showed subgroups of early and late relapse pts. Baseline levels of the CYFRA 21-1 and CEA biomarkers identified a higher number of pts who were likely to recur within the first year and might benefit from closer surveillance. The CYFRA 21-1 assay is currently not cleared or approved for use in the USA.

Background:
The UK National Lung Cancer Audit has been collecting, analysing and reporting data on the management of lung cancer patients for 10 years. This abstract summarises the progress made in this period.

Methods:
Hospitals working within the UK National Health Service are invited to submit data to a web portal on all incident cases of lung cancer (and mesothelioma). The dataset covers demographics, referral, investigation, diagnosis, treatment and outcome.

Results:
Clinical and organisational engagement in the audit increased rapidly over the first 5 years such that currently all hospitals submit data on 100% of the expected incident cases, with 93% of cases having stage and performance status recorded. Measures of good practice have shown incremental improvements (e.g. histological confimation rate 68% to 75%, proportion with subtyped NSCLC 64% to 87%, proportion of patients seen by a specilaist nurse 51% to 84%, proportion receiving anti-cancer treatment 45% to 60%. The surgical resection rate in histologically-confirmed NSCLC has risen from 14% to 23% in keeping with other data sources, reinforcing the suggestion that these improvements reflect real changes in practice rather than just better data. Survival has improved in patients with early stage disease and good PS as previously published utilising the audit data (Khakwani et al 2013). Moreover, overall survival in the whole cohort appears to be improving when clinical features (age, sex, stage PS) are taken into acocunt as shown in Table 1.

*Adjusted for age, sex, stage and PS

Year	HR*	CI
2008	1.0	-
2009	0.97	0.96-0.99
2010	0.96	0.94-0.98
2011	0.90	0.90-0.93
2012	0.88	0.87-0.90
2013	0.87	0.85-0.89

Despite these overall improvements in process and outcome, there remains a variatin in ractice across organisations that perists after adjustment for case-mix (example Figure 1). Figure 1



Conclusion:
The NLCA has been instrumental in driving improvements in lung cancer care in the UK. Future comparative audit projects spanning national and international boundaries hold the promise of further insights into variations in care and improvement in outcomes for our patients.

Background:
Epidermal growth factor receptor (EGFR) mutations occur in up to 50% of Asian patients with non-small cell lung cancer (NSCLC). Treatment of advanced NSCLC patients with EGFR-tyrosine kinase inhibitors (EGFR-TKI) confers a significant survival benefit. This study assessed the efficacy and safety of chemotherapy with or without icotinib in patients undergoing resection of stage IB to IIIA EGFR-mutated NSCLC.

Methods:
Patients with surgically resected stage IB (with high risk factors) to IIIA EGFR-mutated NSCLC were randomly assigned (1:1) to one of two treatment plans. One group received four cycles of platinum-based doublet chemotherapy every three weeks, and the other received platinum-based chemotherapy supplemented by a consolidation therapy of orally administered icotinib (125 mg thrice daily) two weeks after chemotherapy for four to eight months, or until the occurrence of disease relapse, metastasis or unacceptable icotinib or chemotherapy toxicity. The primary endpoint was disease free survival (DFS).

Results:
39 patients were enrolled between February 2011 and December 2012. 21 patients were assigned to the combined chemotherapy plus icotinib treatment group, while 18 patients received chemotherapy only. DFS at 12 months was 100% for icotinib-treated patients and 88.9% for chemotherapy-only patients (p = 0. 122). At 18 months DFS for icotinib-treated vs. chemotherapy-only patients was 95.2% vs. 83.3% (p = 0. 225), respectively, and at 24 months DFS was 90.5% vs. 66.7% (p = 0. 066). In the Cox proportional hazards model, the treatment groups and pTNM stage showed a statistically significant, the HR was 0.136 (95%CI: 0.022-0.829, p = 0.030) and 5.498 (95%CI: 1.333-22.673, p = 0.018) respectively. Adverse chemotherapy effects predominantly presented as gastrointestinal reactions and marrow suppression, and there was no significant difference between the two treatment groups. Patients in the chemotherapy plus icotinib treatment group showed favorable tolerance to oral icotinib.Figure 1



Conclusion:
The results suggest that, firstly, chemotherapy plus orally icotinib displayed a longer DFS compared with chemotherapy only, and secondly, patients receiving extra orally icotinib showed favorable tolerance without severe side effects. Nonetheless, our results are promising and future trials with larger sample sizes could confirm our current data.

Background:
In the U.S., racial/ethnic and gender differences in treatment and survival of early stage non-small cell lung cancer (NSCLC) have been reported. These findings come largely from analyses of SEER-Medicare data, which inherently exclude younger and managed care patients, up through 2005. Whether such differences exist in an integrated health care system, other than the U.S. Military Health System and Veterans Health Administration, has not been comprehensively examined.

Methods:
Using electronic health record and cancer registry data from Kaiser Permanente Northern California, a fully integrated health care system, we identified a cohort of 1,566 patients of non-Hispanic White, Asian/Pacific Islander, Black, or Hispanic race/ethnicity diagnosed with incident stage I/II NSCLC at ages 21 to 80 years from 2004 to 2011. Patients were followed from NSCLC diagnosis to health plan termination, death, or study end (through 2013), whichever occurred earliest. We examined whether the following prognostic factors (at NSCLC diagnosis, unless otherwise specified), in addition to 3-year overall survival, differed statistically (p<0.05) by race/ethnicity or gender: age; marital status; smoking history; comorbidity score; tumor stage, size, and histology; and receipt, modality, and timing of initial treatment. Using multivariable Cox regression, we further examined the extent to which race/ethnicity and gender were associated with overall survival after accounting for other prognostic factors.

Results:
Our cohort included 1137 non-Hispanic Whites (482 men, 655 women); 232 Asian/Pacific Islanders (95 men, 127 women); 126 Blacks (52 men, 74 women); and 71 Hispanics (36 men, 35 women). The median age at diagnosis was 68 years. Overall, 92% were treated (89% of those treated by surgery), within 1.8 months post-diagnosis on average, and 41% died during 69,894 person-years of follow-up (median=3.3 years). Comparing across the race/ethnicity groups, non-Hispanic Whites were generally older at diagnosis, while Asian/Pacific Islanders were more likely to be married, never or former smokers, have a lower comorbidity score, and diagnosed with adenocarcinoma. The group most commonly treated with surgery was Asians/Pacific Islanders (87.5%), followed by Hispanics (81.7%), non-Hispanic Whites (79.9%), and Blacks (65.1%), with 3-year overall survival probabilities of 77%, 73%, 69%, and 63%, respectively. Compared to women, men were more likely to be married, former or current smokers, have a higher comorbidity score, and have a tumor of higher stage, greater size, and squamous cell histology, although both their receipt of surgery (women: 82%, men: 78%) and 3-year overall survival probabilities (women: 71%, men: 69%) were similar. After accounting for age, marital status, smoking history, comorbidity score, tumor characteristics, and receipt, modality, and timing of initial treatment, overall survival was similar for Asian/Pacific Islanders (hazard ratio (HR): 0.90; 95% confidence interval (CI): 0.69-1.17), Hispanics (HR: 0.96; 95% CI: 0.66-1.42), and Blacks (HR: 0.99; 95% CI: 0.75-1.31) compared to non-Hispanic Whites, and for men (HR: 0.95; 95% CI: 0.80-1.13) compared to women.

Conclusion:
Among early stage NSCLC patients in our integrated health care system, we found racial/ethnic differences in treatment, but no racial/ethnic or gender differences in overall survival after accounting for treatment and other prognostic factors.

Background:
Second primary lung cancer (SPLC) is an important cause of death in survivors of head and neck squamous cell cancer (HNSCC). The goal of this Dutch population study was to compare treatment patterns and outcomes in early-stage SPLC after HNSCC.

Methods:
Details on all patients in a population of 16 million diagnosed with lung cancer between 1997 and 2011 were obtained from the Netherlands Cancer Registry. After excluding patients with a history of other malignancies, patients were dichotomized with a primary lung cancer or a SPLC after HNSCC. The latter included oral cavity, oropharynx, larynx, and hypopharynx sub-sites. Baseline characteristics of early-stage primary and SPLC were compared using the chi-square, fisher’s exact, or t-test, where appropriate. After stratifying patients into five consecutive 3-year time periods, the Chi-Square Trend test was used to determine trends in treatment patterns over time. Overall survival was calculated using the Kaplan-Meier method, and the log-rank test used to assess differences in survival. 30- and 90-day treatment related mortality were calculated. To assess for stage migration due to routine availability of PET-staging, as well as the availability of stereotactic ablative radiotherapy (SABR), outcomes were analyzed before and after 2005. All statistical tests were two-sided and considered significant when p<0.05.

Results:
Of the 153,330 lung cancer patients, 19,501 with a history of a non-HNSCC primary cancer were excluded from the analysis. Of the 133,829 remaining patients, 2,556 (2%) represented a SPLC following HNSCC. SPLC patients were more likely to present in stage I (27% versus 16%, p<0.01) rather than stage IV (34% versus 44%, p<0.01). For early-stage SPLC, initial HNSCC anatomical subsites were most commonly larynx (53%) and oral cavity (24%). Treatment for early-stage SPLC included surgery (53%), radiotherapy (RT, 33%), or best supportive care (14%). The proportion of RT patients undergoing SABR was unknown. When compared to surgery, early-stage SPLC patients receiving any-form of RT tended to be older, with more advanced T-stage disease, poorly differentiated histology, and lower rates of pathologic diagnosis (all p<0.01). The proportion of all early-stage lung cancer patients receiving surgery over time remained stable in the primary setting (range: 59-63%, p=0.69), but decreased for early-stage SPLC patients (range: 68-42%, p<0.01). The use of RT increased over time for both primary (range: 21-30%, p<0.01) and early-stage SPLC patients (range: 23-43%, p<0.01). 30- and 90-day treatment related mortality rates were higher in surgical versus RT patients in both pre-2005 (3.8%, 8.6% versus 4.0%, 8.0%) and post-2005 (2.3%, 4.0% versus and 0%, 3.2%) eras. Overall, early-stage SPLC surgical patients had improved survival when compared to RT patients (p<0.01). In the post 2005 era, however, survival was similar for these two modalities (p=0.13).

Conclusion:
In survivors of HNSCC who develop early-stage SPLC, RT deserves attention as an alternative gold standard to surgery. Previous studies indicated that a majority of RT delivered for early-stage NSCLC after 2006 was SABR [Palma D, 2010]. Despite negative selection of poorer baseline characteristics, use of RT resulted in comparable survival and lower post-treatment mortality when compared to surgery in the modern era.

Background:
We report safety and efficacy results for an institutional prospective phase II trial for medically-inoperable patients with centrally-located early-stage non-small cell lung cancers receiving dose escalated SBRT. The Phase II objectives were to determine the overall survival and patterns of local failure.

Methods:
Eligible patients with biopsy-proven NSCLC within 2cm of the proximal bronchial tree (RTOG definition) were enrolled on an IRB-approved institutional clinical trial between 2006-2015. All patients were medically inoperable. The Phase I portion consisted of 4 radiation dose levels using 5 fraction regimens. Dose levels were 9, 10, 11, and 12 Gy/fraction. Phase I was previously reported (ASTRO 2011). Based on an early analysis of efficacy, the Phase II radiation dose was 11 Gy x 5 fractions.

Results:
64 patients were enrolled to the trial; 23 to Phase I and 41 to Phase II. The median follow up for phase II patients alive is 6.2 months (range 1.3-46.3 months). 41 patients are eligible for toxicity analysis and 37 with at least 1 post-treatment visits are eligible for efficacy. Regarding treatment-related toxicity, 1 patient experienced acute Grade 3 hypoxia (2.4%; 95% CI 0.1-12.8%), 3 patients developed late Grade 3, 2 had late grade 4, and 1 had late grade 5 events. The grade 4 events were lung atelectasis resulting in hospitalization and dyspnea, respectively. The grade 5 event was fatal hemoptysis in a patient with tumor involving the pulmonary artery. The one-year local lobar recurrence rate using 11 Gy x 5 fractions is 4.6% (95% CI 0.7-13.6%). The one-year OS is 81.2% (60.0-91.8%).The predominant causes of death were distant metastasis (N=6), intercurrent illness without recurrence (N=6), and secondary lung cancer (N=2). One patient is alive with gastric cancer. Two patients developed nodal recurrence and two developed local failures.

Conclusion:
SBRT for central tumors using 11 Gy x 5 fractions was tolerable, but can contribute to severe toxicity as shown by others where tumor involves the pulmonary vasculature. The lobar tumor control was excellent using 11 Gy x 5 fractions. The results of RTOG 0813, which was methodologically based on this trial, may help to clarify the preferred dose for central lesions.

Background:
Radiotherapy dose-escalation trials have achieved inconsistent levels of overall survival (OS) for non-small cell lung cancer (NSCLC). For stage III NSCLC, RTOG-0617 reported poorer OS for 74Gy than for 60Gy delivered in 2Gy fractions with concurrent chemotherapy (median OS 20·3 vs 28·7 months). The phase I/II IDEAL-CRT CRUK funded trial (Sponsor: University College London (C13530/A10424)) of isotoxic dose-escalation delivered mean and maximum doses of 67.5 and 73Gy in 30 fractions over 40 days, equivalent to 69 and 75.6Gy in 2Gy fractions (EQD2), and reported 1- and 2-year OS rates 87.8% (95% CI:80.7-94.9) and 67.1% (95% CI:56.3-78.0) respectively. Here we investigate associations between OS and dose-distributions delivered to heart, left ventricle (LV), lung minus gross tumour volume (lung-GTV) and oesophagus.

Methods:
For 80 of 82 IDEAL-CRT patients, heart, LV, lung-GTV and oesophagus differential dose volume histograms (DVHs) were extracted from planning data using CERR. Since prescribed doses-per-fraction varied, physical DVHs were converted to EQD2s using the linear-quadratic equation with an α/β of 3Gy for heart, LV and lung-GTV, and 1.7Gy for oesophagus. Patient-to-patient DVH variability was efficiently represented using a small number of Varimax-rotated principal components (PCs) which explained 95% of the total variance: four for oesophagus, five each for heart and LV, and fourteen for lung-GTV. OS was modelled from the start of treatment using Cox regression.

Results:
On univariate analysis there is evidence that larger planning target volumes (PTVs) and greater Heart-PC3 and LV-PC4 coefficients are associated with worse OS (see table). Heart-PC3 represented heart volumes receiving doses of 65-75Gy, and LV-PC4 represented LV volumes receiving 1-5Gy. No lung-GTV or oesophageal dosimetric parameters were significantly associated with OS (p-values>0.1). Although OS improved with increasing prescribed dose, this trend did not reach statistical significance. The estimates of these effects did not change markedly after adjusting for other covariates in the multivariate analysis, and the relationship between greater Heart-PC3 and worse OS remained highly significant.

Results (n=80)

Mean values
Parameters Mean Minimum Maximum EQD2 lung-GTV dose 12.1Gy 6.2Gy 18.5Gy PTV 448.6cm[3] 138.7cm[3] 1262.2cm[3] Heart volume receiving >5Gy (V5) 33.9% 0% 99.9% Heart volume receiving >30Gy (V30) 11.3% 0% 47%
Univariate Cox model for OS
Covariate Hazard Ratio 95% Confidence Interval p-value EQD2 prescribed dose 0.951 0.883-1.024 0.185 PTV 1.002 1.000–1.003 0.026 Heart-PC3 1.257 1.070-1.478 0.005 LV-PC4 1.257 0.998–1.584 0.052
Multivariate Cox model for OS
Covariate Hazard Ratio 95% Confidence Interval p-value EQD2 prescribed dose 0.977 0.900-1.060 0.570 PTV 1.001 0.999-1.003 0.179 Heart-PC3 1.228 1.039-1.452 0.016 LV-PC4 1.203 0.943-1.536 0.137

Conclusion:
We found strong evidence of an association between lower OS in IDEAL-CRT patients and heart volumes receiving 65-75Gy. There was some evidence of a negative association between OS and LV volumes receiving 1-5Gy. RTOG0617 has reported a negative relationship between OS and heart volumes receiving greater than 5Gy. Thus OS gains potentially achievable through tumour dose-escalation may be offset by associated heart dose increases. Further studies are required to improve understanding of radiation effects on heart substructures, aiming to identify avoidance structures for possible cardiac-sparing dose-escalated NSCLC treatments.

Background:
Traditionally, sparing the heart in chemo-radiotherapy of locally advanced lung cancer has a low priority compared to the lungs and esophagus. Recently, however, the randomized phase III trial RTOG 0617 showed that the volume of the heart receiving a dose of at least 5Gy (V5) was associated with a lower overall survival (OS). The aim of the current study is to validate this in an independent database.

Methods:
Patients treated with IMRT (24x2.75Gy with daily low-dose cisplatin) at our hospital between 2006 and 2014 were retrospectively selected. For the heart both mean dose and Vx denoting the volume receiving x Gy or more (x in range 5-50Gy with 5Gy increments) were calculated. Associations of these parameters with OS were evaluated using univariate and multivariate proportional hazards analysis. In multivariate analysis we separately paired the total GTV (primary tumor plus involved lymph nodes) to Vx and mean dose.

Results:
375 pts were available for analysis. Median follow up was 16 months and median OS was 26 months. Using univariate proportional hazard modeling mean dose and all Vx for x<40Gy were significantly associated (p<0.05) with OS. For V5, which was most significant in the analyzed set, the hazard ratio (HR) was 1.008. When pts are split at the median V5 = 37.0%, the median OS was 29 ± 2.5 months versus 19 ± 2.4 months for pts below and above the median respectively (p=0.03, Log Rank). Similarly, the figure illustrates significant separation in Kaplan-Meier plots of OS with the pts divided in V5 quartiles. In the multivariate analysis the correlation between GTV (median volume 109 cc) and mean dose or Vx was less than 0.15, indicating that a higher heart dose is not the effect of larger tumor volumes and hence a worse survival due to more advanced decease. Both GTV (p<0.001, HR=1.001) and V5 (p=.003, HR=1.007) were significant in multivariate analysis as was the case with GTV (p<0.001, HR=1.001) and mean dose (p=0.033, HR=1.018).

Conclusion:
For pts treated with chemoradiation the dose received by the heart is strongly associated with overall survival. Our results are in accordance with the results of RTOG 0617 [1] for the V5 with similar HR despite the different fractionation scheme and chemo regimen. This indicates that cardial toxicity might be more important in lung cancer patients treated with chemoradiation than previously anticipated. Consequently, better sparing of the heart potentially improves outcome. [1] Bradley et.al. J Clin Oncol 31, 15 pp. 7501

Background:
Thoracic radiotherapy plays an important role in the treatment of lung cancer. However, the safety of thoracic radiotherapy delivery is restricted to the risk of radiation pneumonitis(RP), which is the major dose limiting toxicity for patients undergoing thoracic radiotherapy. Few studies to date have assessed risk factors associated with the development of RP in lung cancer patients treated with volumetric modulated arc therapy (VMAT). This study aimed to report the RP incidence and clinical and dosimetric risk factors associated with RP in lung cancer patients treated with VMAT at a single institution.

Methods:
In this retrospective study, lung cancer patients treated with VMAT from 2013 through 2015 were reviewed. RP was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version.4.0. Clinical factors and dosimetric parameters were evaluated using logistic multivariate regression for estimating the correlation with RP. The results were considered statistically significant when the p-value was<0.05.

Results:
Thoracic radiotherapy with VMAT was administered in 77 lung cancer patients. Of these patients, 58 were men and 19 were women, with a median age of 60 years (range 22-84 years); 25 patients received concurrent chemoradiotherapy, and the median radiation dose was 60Gy (range 45-64Gy). VMAT plans were performed with single arc in 9 patients, double in 55 patients, triple in 4 patients, and the mean (±SD) delivery time was 189.1s±42.0s. VMAT allowed us to respect most planning objectives on target volumes and organs at risk, for PTV V~95% ~= 96.8 ± 6.1%; for lung V~5~ = 41.3 ± 8.7%, V~10~ = 29.9 ± 7.1%, V~20~ = 20.9 ± 5.7%, mean dose=1150.9±277.6Gy. With regard to acute RP after thoracic radiotherapy, 10.4% were grade 1 (G1), 16.9% G2, 9.1% G3, 2.6% G5. The overall incidence rate of symptomatic RP (grade ≥ 2 by CTCAE) was 28.6% in the entire cohort. Based on the clinical data and dosimetric parameters analysis, factors predictive of symptomatic RP were lung volume receiving ≥10Gy (V~10~) [OR: 1.39, 95% CI 1.07–1.80, p=0.014], PS score[OR:5.44, 95% CI 1.29–23.08, p=0.021], concurrent chemotherapy[OR:3.85, 95% CI 1.07–13.86, p=0.039]and CRP changing level[OR:1.06, 95% CI 1.01–1.12, p=0.014].

Conclusion:
VMAT, a novel technique, provides a viable option for the thoracic radiotherapy of lung cancer with acceptable toxicities. However, for patients with higher V~10~, poorer PS score, greater increasing level of CRP and undergoing concurrent chemotherapy, VAMT technique should be administrated with cautions. Several molecular biomarkers have been reported that correlated with the development of RP, which will be tested in our further analysis.

Abstract not provided

Background:
Thoracic radiotherapy is a usual treatment for lung cancer; either at early-stages (stereotactic mode) or at locally advanced stages (conventional radiotherapy mode). Thoracic irradiation appears to have little impact on lung volume such as forced expiratory volume in one second (FEV1) or forced vital capacity (FCV). By contrast, carbon monoxide diffusing capacity (TLCO) may be altered under thoracic radiotherapy. Pulmonary diffusion may be also evaluated by the NO (azote monoxide) diffusion capacity (TLNO). Moreover, double assessment of NO and CO diffusing capacities open the way to understand if alteration of lung diffusion is due to alveolar membrane and/or a pulmonary capillary alteration. CONORT aims at measuring pulmonary function tests (PFTs), in particular the CO and NO diffusing capacity, during thoracic radiotherapy.

Methods:
Prospective multicenter study. CONORT study was approved by the Lyon Sud-Est IV ethics committee and the database was declared to the national information registry authority as required by French laws. Overall 112 patients must be included to estimate a difference of 15% in diffusing capacity test, with a 90% power and a 5% alpha risk. All consecutive patients treated by thoracic radiotherapy in Lyon Sud Hospital were included regardless of histology and radiotherapy technique. PFTs including double diffusion are performed by the same operator and using the same technic, before-, during-, at the end-, six weeks after- and six months after- thoracic irradiation. All included patients gave their consent. Results at PFTs were expressed in % of theoretical value (%th), and were compared using Student t test.

Results:
Between 1[st] February 2014 and 14 April 2015, 88 patients were included and 62 have been analyzed. Patients were male in 73%, mean age was 67.4 years. Radiotherapy technique was intensity-modulated radiation therapy (IMRT) in 61%, stereotactic radiotherapy (SBRT) in 32%, and 3D conformal radiotherapy in 7%. Mean pretreatment FEV1 was 2.06L (78.9% of the standard), mean FCV was 3.17L (94.9%), mean TLCO was 16.5 (64.7%) and mean TLNO was 72.7 (60.3%). FEV1 and FCV were stable during and after radiotherapy. However, mean TLCO decreased by 4.4% (P=0.01) between first and fourth PFT, mean DLNO decreased by 4% (P=0.001) between first and second PFT, mean VC (capillary lung volume) decreased by 6.24% between first and fourth PFT (P=0.011), and DM (membrane diffusing capacity) decreased by 3.6% between first and second PFT (P=0.001).

Conclusion:
CONORT is the first study evaluating the potential impact of thoracic radiotherapy on double measurement of lung diffusing capacity. These preliminary results showed that thoracic radiotherapy has little impact on lung volumes. However, lung diffusion decreases, initially by membrane alteration and then by capillary alteration. Results at 6 months showed that this alteration is fully recovered. Updated data will be presented at meeting.

Background:
The study aimed at investigating the feasibility of shrinking field after complete or partial response during Chemoradiothrapy without surgery for stage III non-small cell lung cancer (NSCLC).

Methods:
This retrospective study was carried on 97 consecutive patients with stage III non-small cell lung cancer (NSCLC), who were good responders to cheomoradiation without surgery between September 2009 and November 2014. Computed tomography scans were performed after 40-50 Gy to evaluate the curative effect. Fifty three-dimensional-conformal treatment or intensity-modulated radiation therapy were redelineated to shrink the radiation volume once or twice during conventionally fractionated radiotherapy, leading to a boost of 6-20Gy delieverd to the shrunk PTV. The gross tumor volume (GTV) and planned target volume (PTV) were messured. The acute symptomatic irradiation-induced pneumonia(ASIP) as well as first progression patterns and overall survival were investigated through follow-up.

Results:
Among 97 patients who obtained complete or partial response with median total dose of 60.0 Gy (range, 46.0-70.0 Gy), 50 patients received shrinking field radiation therapy with a median 184.24 cm[3 ](range, 28.1- 449.7cm[3]) reduction of PTV between the first and last plan. The primary GTV and PTV in shrinking field group was greater than that in non-shrinking field group, as well as the 59Gy-greater radiation dose rate(GTV, 116.8 cm[3] vs 102.9 cm[3 ]; PTV, 493.0 cm[3 ]vs 458.0 cm[3]; 59Gy-greater dose rate, 70 % vs 61.7 %). The incidence of ASIP was 20.6%(20/97) for all the population, shrinking field group of 18%(9/50) and non-shrinking field group of 23.4%(11/47). Fifteen patients progressed locoregionlly, 12 distantly and 3 in both patterns in shrinking field group, while 22 locoregionlly, 16 distantly and 3 in both patterns in non-shrinking field group. Four regional-progression located out of PTV in both groups. The locoregion-progression rate and out-PTV rate were not significant difference(60% vs 61%, P=0.934; 63.3% vs 56.1%, p=0.54). As compared with non-shrinking field group, shrinking field had a similar overall survival(median OS, 29 mouths vs 30 mouths, P=0.546), an improved median progression free survival (median PFS, 19 mouths vs 14 mouths, P=0.945) and a lower incidence of acute irradiation-induced pneumonia, but they were all not statistically significant.

Conclusion:
Shrinking field and dose escalation for good responders during chemoradiotherapy seem safe with acceptable toxicity and outPTV relapse, especially for the lung cancer with a bulky mass. More prospective trials are needed to validate these results.

Background:
Accelerated repopulation of tumour cells causes inferior local control in locally advanced NSCLC (non-small cell lung cancer). Hypofractionated radiation schedule with a shorter overall treatment time may address this issue. The current study was aimed at evaluating the feasibility and efficacy of using hypofractionated radiotherapy with concurrent chemotherapy after neoadjuvant chemotherapy in locally advanced NSCLC.

Methods:
Thirty patients of locally advanced NSCLC were enrolled in this randomized controlled study and were allocated to one of the two treatment arms between October 2011 and July 2013. Arm A (n=15) received neoadjuvant chemotherapy (NACT) (paclitaxel 200mg/m2 and carboplatin AUC 5) followed by external radiotherapy (EBRT) (60Gy/30fractions/6weeks). Arm B (n=15) received the same NACT followed by EBRT (48Gy/20fractions/4weeks) with concomitant chemotherapy (cisplatin 30mg/m2 weekly). Quality of life analysis was done using EORTC (European organization for Research and Treatment in Cancer) QLQ C30 and LC13. Toxicity scoring was done using CTCAE (Common Terminology Criteria for Adverse Events) version 3.0. The treatment response between two arms was computed using Fisher’s exact test. The difference in QOL parameters were compared by Wilcoxon signed rank test and Mann-Whitney U test for paired and unpaired samples. Survival time was estimated by Kaplan–Meier survival analysis. Survival pattern was compared using the log-rank test. Factors which had p value <0.25 in univariate analysis were subjected to multivariate analysis using Cox regression analysis. Statistical analysis was carried out using Stata software version 12.0.

Results:
The overall response rate at the time of first follow-up for arm A was 54.55% as compared to 85.71 %( p=0.08) in arm B. At median follow-up duration of 12 months the ORR was numerically superior in arm B though not statistically significant 33% vs 47%).The median PFS in arm A and B were 9.2 and 17.23 months respectively [hazard ratio 2.92 (95% C.I: 1.02-9.11); p=0.05]. No significant difference was discernible in OS between two arms on multivariate analysis. Social functioning showed a trend towards improvement while alopecia showed a trend towards worsening in arm B. The most common grade 3/4 hematological and non-hematological toxicity were neutropenia peripheral neuropathy and dysphagia (arm A: 3; arm B: 1).

Conclusion:
Hypofractionated radiotherapy with concomitant chemotherapy after NACT is feasible for locally advanced NSCLC. Such management approach can expedite treatment with an acceptable morbidity, patient compliance and quality of life and thus reduces the waiting time, machine load, socio-economic burden in patients which is significant in a developing nation.

Background:
Radiation pneumonitis (RP) is the most worrying complication following high dose radiation therapy (RT) for loco-regionally advanced lung cancer. Intensity modulated radiation therapy (IMRT) and intensity modulated proton therapy (IMPT) are expected to reduce RP compared with conventional RT technique. Adaptive re-plan is usually indicated to accommodate tumor shrinkage and position changes during fractionated RT course. This study is to comparatively evaluate dosimetric differences between RT techniques and interval changes of these parameters assuming that initial IMRT and IMPT plans are continued throughout RT course without adaptive re-plan.

Methods:
Ten patients who were given concurrent chemo-radiotherapy by IMRT (66 Gy/33 fractions, weekly Docetaxel/CDDP #6) for having N3(+) stage IIIB lung cancer were selected. Surrogate rival IMPT plan on each patient was generated to compare with initial IMRT plan. Beam numbers used in IMRT and IMPT were 6-7 and 3. Second CT obtained during 3[rd]-4[th] week for adaptive IMRT plan was used to generate second sets of IMRT and IMPT plans, assuming that adaptive plan had not been done. Differences between initial RT techniques and changes in dosimetric parameters including conformity index (CI), homogeneity index (HI) and dose-volume histogram (DVH) of target and normal organs, which could have occurred by 2 RT techniques, were compared.

Results:
When comparing initial IMRT and IMPT plans, IMPT showed advantageous features over IMRT with respects to median HI (1.08 vs. 1.02), mean doses (D~mean~) to lung, esophagus, and heart, lung volumes receiving 5 Gy (V~5~), 10 Gy (V~10~), 20 Gy (V~20~), 30 Gy (V~30~), and 40 Gy (V~40~) and maximum dose (D~max~) to spinal cord (all p<0.05), respectively. Mean gross tumor volumes (GTV) on initial and second CT’s were 90.9 (48.1~163.7) cm[3] and 52.2 (23.1~89.7) cm[3] and median GTV reduction was 42.2% (51.3%-84.4%). More dosimetric parameters could have changed significantly by IMPT (CI, HI, V~5~, V~10~, V~20~, V~30~, D~mean~ to lung and heart, and D~max~ to spinal cord) than IMRT (CI, HI, V~20~, D~max~ to spinal cord and heart), respectively. Absolute increase in D~max~ to spinal cord was estimated as 0.53 Gy by IMRT and 4.79 Gy by IMPT (p=0.003).

Conclusion:
Impact of GTV regression during RT course and need for adaptive re-plan seem evident. More uncertainties on dosimetric parameters and higher doses to spinal cord are expected by IMPT than by IMRT if re-plan is not applied. Optimal timing and frequency of adaptive plans, however, need to be further evaluated.

Abstract not provided

Background:
Despite the increasing number of elderly patients (p) with unresectable stage III NSCLC p presenting to our clinic, there is no consensus on the therapeutic approach to these p. The comprehensive geriatric assessment (CGA) and the comorbidity measurement are relevant tools to identify p who may benefit from tolerable combinations of concurrent chemoradiation (CRT).

Methods:
Elderly p (≥75 years) with stage III NSCLC underwent multidimensional geriatric assessment (MGA) that incorporated validated instruments to assess comorbidity, polypharmacy, functional status, geriatric syndromes (GS), mood, cognition and vulnerability. P were classified according to the MGA results into 3 risk groups: (1) fit p: independent in all ADL and IADL, no comorbidities and absence of GS; (2) vulnerable p: <3 comorbidities and/or <3 IADL but no ADL disability and absence of GS; (3) dependent p: ≥3 disabilities or presence of GS. P classified into group 1 and 2 were considered candidates for antitumoral treatment, whereas patients into group 3 were candidates to best support care. Clinical, GA and follow-up data were prospectively collected. Overall survival (OS) was calculated using Kaplan-Meier method and the median follow-up time was 13.5 months.

Results:
From July 2008 to November 2014, 54 elderly p with stage III NSCLC were identified. The median age was 80 years (74-87) and most p (93%) were males. The most common histological subtype was squamous cell carcinoma (54%), followed by adenocarcinoma (28%) and NOS (18%). MGA classified 20 p (37%) as fit, 23 p (43%) as vulnerable and 11 p (20%) as dependent. Median number of comorbidities: 4 (0-11); median number of drugs: 6 (0-12); median Karnofsky: 80% (60-100); median Barthel: 95 (80-100); Lawton-Brody Scale (<4/≥4): 18%/82%; Pfeiffer (<4/≥4): 89%/11%; Yesavage test (0/≥1): 54%/46%; 1 (0-10); median GS: 1 (1-3); VES-13 (<3/≥3): 50%/50%. Risk groups 1 and 2 had significantly better median OS (20 and 17.5 months, respectively) as compared with group 3 (7.7 months, p=0.004). The number of p treated with concurrent CRT was higher among fit patients (14; 70%) as compared with group 2 (8; 35%) and 3 (0; 0%). Some fit and vulnerable p did not receive concurrent CRT due to patient and physician decision, tumor not amenable for radiotherapy or comorbid conditions. P treated with concurrent CRT received conventional 3D thoracic radiotherapy (2 Gy/fraction) in combination with carboplatin AUC 2.5 and vinorelbine 15 mg/m2 on days 1, 8, 21 and 29. Overall response rate was 68%. Median OS was 22 months (95% CI 10.6 – 33.6). There were no differences in OS when comparing risk groups 1 and 2 (p=0.446). Adverse events (G3-4): neutropenia, 2p (9%); anemia, 1p (4.5%); thrombocytopenia 1p (3%); febrile neutropenia, 1p (3%); pneumonia, 1p (3%); tracheo-bronchial infection, 3p (14%); asthenia 2p (9%); anorexia 1p (4.5%); diarrhea, 1p (4.5%); radiation pneumonitis, 3p (14%) and oesophagitis 0p (0%). Three p (14%) died due to radiation pneumonitis and 1 p (3%) due to a respiratory infection.

Conclusion:
MGA may help in the selection of elderly p for concurrent CRT and appeared to be a valuable tool to avoid undertreatment of those p.

Background:
To analyze acute esophagitis (AE) in a Chinese population receiving 3D conformal radiotherapy (3DCRT) for non-small cell lung cancer (NSCLC), combined or not with chemotherapy (CT), using the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model.

Methods:
157 Chinese patients (pts) presented with NSCLC received 3DCRT: alone (34 pts) or combined with sequential CT (59 pts) (group 1) or with concomitant CT (64 pts) (group 2). Parameters (TD50, n, and m) of the LKB NTCP model predicting for > grade 2 AE (RTOG grading) were identified using maximum likelihood analysis. Univariate and multivariate analysis using a binary regression logistic model were performed to identify patient, tumor and dosimetric predictors of AE.

Results:
Grade 2 or 3 AE occurred in 24% and 52% of pts in group 1 and 2, respectively (p<0.001). For the 93 group 1 pts, the fitted LKB model parameters were: m=0.15, n=0.29 and TD50=46Gy. For the 64 group 2 pts, the parameters were: m=0.42, n=0.09 and TD50=36Gy. In multivariate analysis, the only significant predictors of AE were: NTCP (p<0.001) and V50, as continuous variable (RR=1.03, p =0.03) or being more than a threshold value of 11% (RR=3.6, p =0.009).

Conclusion:
A LKB NTCP model has been established to predict AE in a Chinese population, receiving thoracic RT, alone or combined with CT. The parameters of the models appear slightly different than the previous one described in Western countries, with a lower volume effect for Chinese patients.

Background:
Brain metastases (BM) develop in 22-55% of patients with locally advanced Non-small cell lung cancer (LA-NSCLC) treated with curative intent. Prophylactic cranial irradiation (PCI) reduces the incidence of BM by40- 60% but is not part of standard practice due to a lack of proven survival benefit and concerns regarding toxicity. This study aimed to determine patient preferences with respect to the survival gain or reduction in BM PCI would need to provide and the amount of toxicity considered acceptable for them to accept PCI.

Methods:
A Discrete Choice Experiment (DCE) was used. Patients undergoing definitive chemoradiation therapy for LA-NSCLC were asked to make 15 hypothetical choices between two alternative PCI treatments at each of two time points (i.e. pre- and post their own treatment). Each alternative PCI treatment was described by four attributes: amount of life gained, ability to care for oneself, loss of memory and the chance of BM. Participants were also given the option of no PCI treatment. The choice data were analysed using multinomial and mixed logit regression models, to indicate the relative importance of improvements in each attribute for treatment preference.

Results:
There were 54 and 46 surveys completed pre- and post-treatment respectively. Participants had a mean age of 63.6 (range 39-82) years, 74% were male. Participants chose to accept PCI versus no PCI in approximately one third of the choices (34.8% pre- and 33.3% post - treatment). Overall, participants preferred a treatment alternative if it was associated with a longer survival, better ability to take care of oneself, lower loss of memory, and lower chance of BM. Before treatment, an increase in survival of more than 6 months was the most important benefit (relative importance weight 61.2), followed by avoiding severe problems with memory (39.4), avoiding severe problems with self-care (30.3), and a 15% reduction in risk of BM (15.0). After treatment, the rank order of importance remained similar but a reduction in the risk of BM became more important, relative to gains in the other attributes. Preliminary analysis suggests if PCI is able to reduce BM risk by 15% and increase survival by >6months, participants have a probability of uptaking PCI of 0.66 pre- and 0.55 post-treatment, even if they are left with severe problems caring for themselves and severe memory loss.

Conclusion:
The majority of patients would accept PCI for an increase in survival >6months, with a reduction in BM by 15%, , even if severe memory/self-care problems occurred. Patients would avoid PCI if it caused severe problems with memory/ self-care versus mild-moderate problems with memory/self-care, when survival gain is less than 6 months. Patients care more about avoiding BM following the completion of therapy.

Abstract not provided